Methods of promoting osteogenesis

ABSTRACT

The invention is directed to methods of bone healing by administering a p38 MAP kinase inhibitor. The invention is directed to methods of treating bone fractures, bone diseases, bone grafting, especially enhancing bone healing following facial reconstruction, maxillary reconstruction, mandibular reconstruction or tooth extraction, enhancing long bone extension, enhancing prosthetic ingrowth, and increasing bone synostosis by administering a p38 MAP kinase inhibitor.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. patent applicationSerial No. 60/406,664 filed 29 Aug. 2002. The contents of that documentare incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The invention is directed to methods of promoting osteogenesis byadministering a p38 MAP kinase inhibitor. More specifically, theinvention is directed to methods of treating bone fractures, bonediseases, bone grafting, especially enhancing bone healing followingfacial-reconstruction, maxillary reconstruction, mandibularreconstruction or tooth extraction, enhancing long bone extension,enhancing prosthetic ingrowth, and increasing bone synostosis byadministering a p38 MAP kinase inhibitor.

[0004] 2. Background

[0005] Bone is subject to constant breakdown and resynthesis in acomplex process mediated by osteoblasts, which produce new bone, andosteoclasts, which destroy bone. Osteoblasts secrete osteoid, theunmineralized organic matrix that subsequently undergoes mineralizationwhich provides strength and rigidity to bone.

[0006] One condition in which enhanced bone formation is required isbone fracture. After a bone fracture, it is desirable to stimulate bonegrowth so as to hasten and complete bone repair. There are approximatelysix million bone fractures in the United States each year. Thecomplication rate associated with fracture healing has been estimated at5-10%. Complications such as non-union, delayed union, and mal-union canoccur. The etiology of the complications remains unknown but certainfactors are known to negatively affect the outcome of fracture healing.These effects include age, diabetes, and NSAID (non-steroidalanti-inflammatory drug) use.

[0007] Fracture healing is a complex process. Preferably the fracturehealing process restores a broken bone to its prior metabolic andmechanical functional state. The initial events that occur following afracture include tissue hypoxia and hematoma formation. The tissuehypoxia and hematoma formation quickly lead to inflammation and edema inthe soft tissues surrounding the fracture site. Cell proliferation soonbegins to occur rapidly in the periosteum (the osteoblast cell layeraround the bone) within the vicinity of the fracture site called thefracture callus. Mesenchymal cell migration falls rapidly during theinflammation phase and it is thought that the fibrin clot formed fromthe hematoma acts as a source for cell attachment at the fracture sitefor the migrating cells. The source of the migrating mesenchymal cellsremains controversial but probably includes circulating mesenchymal stemcells mobilized from the bone marrow, vascular pericytes, andproliferating muscle satellite cells. The cells that have migrated intothe fracture site differentiate into chondrocytes and form acartilaginous matrix. Endochondral ossification progressively proceedsfrom the junction between the osteoblasts that have proliferated fromthe periosteum and the differentiated chondrocytes within the fracturesite so that new bone formed from endochondral ossification fills thefracture callus from the periphery to the actual fracture site.Chondrocytes at the osteoblast-chondrocyte boundary terminaldifferentiate into hypertrophic chondrocytes, express Type X collagen,secrete angiogenic factors, and mineralize the cartilaginous matrix(calcified cartilage). Osteoblasts at the osteoblast-chondrocytejunction secrete new bone. As angiogenesis occurs at this boundary,osteoclasts migrate into the area, resorb the calcified cartilage, whichis then replaced with new bone secreted from the osteoblasts.Ultimately, this process bridges the fracture site and the bone isremodeled based upon the mechanical stresses imposed upon the bone.

[0008] Protein kinases are involved in various cellular responses toextracellular signals. p38 Mitogen-Activated Protein (MAP) kinase (alsocalled p38 kinase or “High Osmolarity Glycerol response kinase” (HOG))is a member of a family of signaling molecules known as theMitogen-Activated Protein kinase (MAP kinase or MAPK) family. Othermembers of the MAP kinase family include the classical MAPKs termedExtracellular signal Regulated Kinases (ERK), which are activated by avariety of mitogenic stimuli as well as differentiation signals, andStress-Activated Protein Kinases (SAPK) (also called Jun N-terminalKinases (JNK)). SAPKs are activated by stresses but not mitogens, likethe p38 MAP kinase.

[0009] p38 MAP kinase is activated by a variety of cellular stressors,including ultraviolet radiation, osmotic shock, and inflammatorycytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-α(TNF-α). Once activated, p38 MAP kinase mediates the induction of mRNAsynthesis for a variety of inflammatory mediators, including IL-1β,TNF-α, IL-6, and cyclo-oxygenase-2 (COX-2).

[0010] Four isoforms of p38 MAP kinase have been identified and aredesignated as p38α, p38β, p387 and p386 (Jiang, Y. et al., J. Biol.Chem. 271:17920-17926 (1996); Kumar, S. et al., Biochem. Biophys. Res.Comm. 235:533-538 (1997); Stein, B. et al., J. Biol. Chem.272:19509-19517 (1997); Li, Z. et al., Biochem. Biophys. Res. Comm.228:334-340 (1996); Wang, X. et al., J. Biol. Chem. 272:23668-23674(1997)). p38α is also referred to as p38. p38β is also referred to asp38-2. p38γ is also referred to as ERK6. These isoforms differ in tissueexpression patterns, substrate utilization, response to direct andindirect stimuli, and susceptibility to kinase inhibitors. For example,one study has demonstrated the activation of p38β MAP kinase results inmyocyte hypertrophy, while the activation of p38α MAP kinase leads tomyocyte apoptosis (Wang, Y. et al., J. Biol. Chem. 273:2161-2168(1998)).

[0011] Inhibition of p38 MAP kinase leads to a blockade on theproduction of both IL-1 and TNF. IL-1 and TNF stimulate the productionof other proinflammatory cytokines such as IL-6 and IL-8 and have beenimplicated in acute and chronic inflammatory diseases and inpostmenopausal osteoporosis (Kimble, R. B. et al., Endocrinol.136:3054-3061 (1995)). Based upon this finding it is believed that p38MAP kinase, along with other MAPKs, have a role in mediating cellularresponse to inflammatory stimuli, such as leukocyte accumulation,macrophage/monocyte activation, tissue resorption, fever, acute phaseresponses and neutrophilia. In addition, MAPKs, such as p38 MAP kinase,have been implicated in cancer, thrombin-induced platelet aggregation,immunodeficiency disorders, autoimmune diseases, cell death, allergies,osteoporosis and neurodegenerative disorders. Other diseases associatedwith IL-1, IL-6, IL-8 or TNF overproduction are set forth in WO96/21654.

SUMMARY OF THE INVENTION

[0012] The invention is directed to a method of promoting osteogenesisin a patient, the method comprising administering a pharmaceuticallyeffective amount of a p38 mitogen activated protein (MAP) kinaseinhibitor to the patient in need of osteogenesis.

[0013] The invention is also directed to a method of treating bonefracture in a patient, the method comprising administering apharmaceutically effective amount of a p38 mitogen activated protein(MAP) kinase inhibitor to the patient in need of treatment of bonefracture. The term “bone fracture” includes, but is not limited to, atraumatic bone fracture or a long-term fracture.

[0014] The invention is also directed to a method of enhancing bonegrafting in a patient, the method comprising administering atherapeutically effective amount of a p38 mitogen activated protein(MAP) kinase inhibitor to the patient in need of enhanced bone grafting.

[0015] The invention is further directed to a method of treating a bonedisease in a patient, the method comprising administering apharmaceutically effective amount of a p38 mitogen activated protein(MAP) kinase inhibitor to the patient in need of treatment of a bonedisease.

[0016] The invention is also directed to a method of reducing boneresorption in a patient, the method comprising administering atherapeutically effective amount of a p38 mitogen activated protein(MAP) kinase inhibitor to the patient in need of treatment of boneresorption, thereby increasing bone mass in the patient.

[0017] The invention is also directed to a method of enhancing bonehealing following facial reconstruction, maxillary reconstruction,mandibular reconstruction or tooth extraction, and to enhancing longbone extension, enhancing prosthetic ingrowth or increasing bonesynostosis in a patient, the method comprising administering atherapeutically effective amount of a p38 mitogen activated protein(MAP) kinase inhibitor to the patient in need thereof.

[0018] The invention is also directed to a method of increasing bonemass in a mammal, the method comprising administering a pharmaceuticallyeffective amount of a p38 mitogen activated protein (MAP) kinaseinhibitor to the mammal in need of increased bone mass.

[0019] The invention is also directed to a method of decreasingosteoclast numbers in a patient, the method comprising administering apharmaceutically effective amount of a p38 mitogen activated protein(MAP) kinase inhibitor to the patient in need of decreased osteoclasts.

[0020] The invention is also directed to a method of increasingchondrocyte differentiation in a patient, the method comprisingadministering a pharmaceutically effective amount of a p38 mitogenactivated protein (MAP) kinase inhibitor to the patient in need ofincreased chondrocyte differentiation.

[0021] The invention is further directed to a method of acceleratingcalcified cartilage formation in a patient, the method comprisingadministering a pharmaceutically effective amount of a p38 mitogenactivated protein (MAP) kinase inhibitor to the patient in need ofaccelerated calcified cartilage formation.

[0022] The invention is also directed to a method of increasing orenhancing the rate of bone growth in a mammal, the method comprisingadministering a therapeutically effective amount of a p38 mitogenactivated protein (MAP) kinase inhibitor to the mammal in need ofincreased or enhanced rate of bone growth.

BRIEF DESCRIPTION OF THE FIGURES

[0023] FIGS. 1A-1I. Radiographs from control rats at 4 weekspost-fracture. FIG. 1A. Rat 65. FIG. 1B. Rat 67. FIG. 1C. Rat 81. FIG.1I). Rat 87. FIG. 1E. Rat 92. FIG. 1F. Rat 98. FIG. 1G. Rat 109. FIG.1H. Rat 114. FIG. 1I. Rat 118.

[0024] FIGS. 2A-2F. Radiographs from rofecoxib treated rats at 4 weekspost-fracture. FIG. 2A. Rat 80. FIG. 2B. Rat 96. FIG. 2C. Rat 97. FIG.2D. Rat 104. FIG. 2E. Rat 107. FIG. 2F. Rat 123.

[0025] FIGS. 3A-3E. Radiographs from p38 MAP kinase inhibitor, once perday, treated rats at 4 weeks post-fracture. FIG. 3A. Rat 60. FIG. 3B.Rat 61. FIG. 3C. Rat 78. FIG. 3D. Rat 84. FIG. 3E. Rat 94.

[0026] FIGS. 4A-4H. Radiographs from p38 MAP kinase inhibitor, twice perday, treated rats at 4 weeks post-fracture. FIG. 4A. Rat 64. FIG. 4B.Rat 68. FIG. 4C. Rat 85. FIG. 4D. Rat 90. FIG. 4E. Rat 95. FIG. 4F. Rat102. FIG. 4G. Rat 108. FIG. 4H. Rat 115.

[0027] FIGS. 5A-5C. Graphical representation of the mechanical testingdata at 4 weeks post-fracture. FIG. 5A. Normalized peak torque at 4weeks post-fracture. FIG. 5B. Normalized torsional rigidity at 4 weekspost-fracture. FIG. 5C.

[0028] FIGS. 6A-6D. Histological analysis of fracture healing in drugtreated rats at 2 weeks post-fracture. FIG. 6A. Control. FIG. 6B.Rofecoxib. FIG. 6C. p38 MAP kinase inhibitor, once per day. FIG. 6D. p38MAP kinase inhibitor, twice per day.

[0029]FIG. 7. Histological analysis of the fracture callus of p38 MAPkinase inhibitor treated rat.

[0030] FIGS. 8A-8E. Histological analysis of growth plate morphology ofdrug treated rats. FIG. 8A. Control, at 2 weeks. FIG. 8B. Rofecoxib, at2 weeks. FIG. 8C. p38 MAP kinase inhibitor, once per day, at 2 weeks.FIG. 8D. p38 MAP kinase inhibitor, twice per day, at 2 weeks. FIG. 8E.p38 MAP kinase inhibitor, twice per day, at 4 weeks.

[0031]FIG. 9. Histological analysis of cartilage and bone destriction inearly stage arthritis.

[0032] FIGS. 10A-10D. FIG. 10A is a graphical representation of clinicalmanifestations of arthritis over time. FIG. 10B is a graphicalrepresentation of cartilage oligo matrix protein levels in native,control and treated populations. FIG. 10C is a histological analysis ofbone and cartilage destruction in advanced stage arthritis. FIG. 10D isa graphical representation of osteoclast numbers in advanced stagearthritis.

DETAILED DESCRIPTION OF THE INVENTION

[0033] Osteogenesis

[0034] It has been found that inhibition of p38 MAP kinase activity canprovide beneficial effects regarding osteogenesis, especially whenregarding bone deficits, bone diseases, fractures, grafting, boneresorption, and also beneficial effects in osteogenesis followingelective or non-elective bone surgery, especially cosmetic surgeryincluding facial reconstruction, maxillary reconstruction or mandibularreconstruction, osteogenesis following tooth extraction, enhancing longbone extension, enhancing prosthetic ingrowth, and increasing bonesynostosis.

[0035] The invention is directed to a method of osteogenesis in apatient by administering a pharmaceutically effective amount of a p38MAP kinase inhibitor to a patient in need of bone healing. By “bone” isintended the dense, semi-rigid, porous, calcified connective tissueforming the major portion of the skeleton of most vertebrates,comprising a dense organic matrix and an inorganic, mineral component.Bone is any of numerous anatomically distinct structures making up theskeleton of a vertebrate. The term “osteogenesis” refers to the netdevelopment and net formation of bone, including, without limitation thepromotion of new bone growth and/or the alevation of bone resorption. By“bone healing” is intended restoring a bone and, optionally, thesurrounding cartilage to, or to be closer to, their original or intendedphysical and mechanical properties when compared to such propertiespossessed by the bone prior to the start of such healing and/or prior tothe injury, pathological destruction, pathological deterioration,surgical destruction, or surgical deterioration of the bone.

[0036] A “pharmaceutically effective amount” is intended an amount of acompound that, when administered to a mammal for treating a condition,disorder or disease, is sufficient to elicit a cellular response that isclinically significant, without excessive levels of side effects. See,“Formulations and Methods of Administration” section, infra, for furtherdetails.

[0037] “Mammal” refers to any animal classified as a mammal, includinghumans, domestic and farm animals, and zoo, sports, and pet companionanimals such as a household pet and other domesticated animal such as,but not limited to, cattle, sheep, ferrets, swine, horses, poultry,rabbits, goats, dogs, cats and the like. Preferred companion animals aredogs and cats. Preferably, the mammal is human.

[0038] A “patient” is intended a mammal, preferably a human, in need oftreatment of a condition, disorder or disease.

[0039] In one aspect of bone healing, the invention is directed to amethod of treating or increasing the rate of healing of bone fracture ina patient by administering a pharmaceutically effective amount of a p38MAP kinase inhibitor to a patient in need of treatment or increase inthe rate of healing of bone fracture.

[0040] The terms “treat” and “treatment” refer to both therapeutictreatment and prophylactic or preventative measures, wherein the objectis to prevent or slow down (lessen) an undesired physiologicalcondition, disorder or disease or obtain beneficial or desired clinicalresults. For purposes of this invention, beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms;diminishment of extent of condition, disorder or disease; stabilized(i.e., not worsening) state of condition, disorder or disease; delay orslowing of condition, disorder or disease progression; amelioration ofthe condition, disorder or disease state, remission (whether partial ortotal), whether detectable or undetectable; or enhancement orimprovement of condition, disorder or disease. Treatment includeseliciting a cellular response that is clinically significant, withoutexcessive levels of side effects. Treatment also includes prolongingsurvival as compared to expected survival if not receiving treatment.

[0041] By “bone fracture” is intended a complete or incomplete break,rupture or crack of a bone. Diagnosis of fractures normally depends uponclinical examination and radiological findings. In the invention, bonefractures include, but are not limited to, traumatic fractures,long-term fractures, and pathological fractures.

[0042] “Traumatic fracture” refers to an immediate fracture, whichinvolves a supraliminal trauma with a degree of local violence thatexceeds the natural elasticity of the bone. It can be accompanied bysimultaneous injury to the soft tissues and very often the skin. Atraumatic fracture can be closed (the adjacent soft tissues can beinjured but the covering soft parts are largely preserved). A traumaticfracture can also be open (the broken ends of the bone are freed byextensive soft tissue injury so that pathogens from outside can enterthe wound directly).

[0043] “Long-term fracture” refers to a chronic fracture, fatiguefracture, stress fracture or spontaneous fracture type I.

[0044] “Pathological fracture” refers to a spontaneous fracture type II.A pathological fracture arises spontaneously, without adequate trauma toaccount for it. The bone may have been previously damaged, either bysystemic disease (e.g., osteoporosis, osteodystrophy, or Paget'sosteitis deformans) or by a local bone lesion (e.g., metastasis,radio-osteonecrosis, or bone tumor). See, Adler, Claus-Peter, BONEDISEASES, p. 114 (Springer-Verlag, Germany 2000).

[0045] Fractures also include, but are not limited to, oblique torsionfracture, transverse fracture, comminuted fracture, compressionfracture, rib fractures, creeping fracture, and fractured femoral neck(Adler, Claus-Peter, BONE DISEASES, Springer-Verlag, Germany (2000)).

[0046] Fracture healing includes primary fracture healing and secondaryfracture healing. Primary fracture healing involves (1) internal contactof the bone ends, (2) uninterrupted immobility of the part, and (3) anadequate blood supply. Secondary fracture healing involves localinflammation and development of a callus (Adler, Claus-Peter, BONEDISEASES, Springer-Verlag, Germany (2000)).

[0047] The invention is also directed to a method of treating orincreasing the rate of bone grafting in a patient by administering atherapeutically effective amount of a p38 MAP kinase inhibitor to apatient in need of treatment or increased rate of bone grafting. By“bone grafting” is intended bone implantation or transplantation by,e.g., autograft, allograft, xenograft, demineralized bone, synthetic andnatural bone graft substitutes, such as bioceramics and polymers, andosteoinductive factors. The purposes of bone grafting include, but arenot limited to, enhancing healing in, e.g., delayed union or nonunionfractures, to replace areas of bone loss arising from neoplasiaexcision, osteomyelitis, trauma or cysts, and stimulating bone fusion inarthrodeses.

[0048] The invention is directed to a method of increasing bonesynostosis in a patient by administering a therapeutically effectiveamount of a p38 MAP kinase inhibitor to a patient in need thereof. Thebone synostosis can be, but is not limited to, a vertebral synostosis.

[0049] The invention is also directed to a method of increasing oraccelerating osteogenesis, especially following facial reconstruction,maxillary reconstruction, mandibular reconstruction or tooth extractionby administering a p38 MAP kinase inhibitor to a patient in needthereof. The invention is also directed to a method of enhancing longbone extension or enhancing prosthetic ingrowth in a patient byadministering a therapeutically effective amount of a p38 MAP kinaseinhibitor to a patient in need thereof. The p38 MAP kinase inhibitorscan be used in promotion of osteogenesis in plastic surgery, stimulationof bone ingrowth into non-cemented prosthetic joints and dentalimplants, treatment of periodontal disease and defects, and other toothrepair processes.

[0050] The invention is also directed to a method of treating a bonedisease in a patient by administering a pharmaceutically effectiveamount of a p38 MAP kinase inhibitor to a patient in need of treatmentof a bone disease. “Bone disease” refers to a disorder or conditionrelating to abnormality of the bone. Bone diseases that can be treatedaccording to the invention, by increasing bone mass or bone growthinclude, but are not limited to, osteoporosis, arthritis,osteoarthritis, periodontal disease, alveolar bone loss, osteotomy boneloss, childhood idiopathic bone loss, curvature of the spine, and lossof height. Destructive bone disorders that can be treated according tothe invention include, but are not limited to, osteoporosis,osteoarthritis and osteolytic lesions such as those caused by neoplasticdisease, radiotherapy, or chemotherapy.

[0051] Bone diseases can be caused by a condition which presents withlow bone mass, a bone deficit, or a cartilage defect. By “bone mass” isintended bone mass per unit volume. A condition which presents with lowbone mass is a condition where the level of bone mass is below the agespecific normal level as defined in standards in “Assessment of FractureRisk and its Application to Screening for Postmenopausal Osteoporosis,”Report of a World Health Organization Study Group, World HealthOrganization Technical Series 843 (1994). A bone deficit is an imbalancein the ratio of bone formation to bone resorption, such that, ifunmodified, the subject will exhibit less bone than desirable, or thesubject's bones will be less intact and coherent than desired. Bonedeficit can also result from fracture, from surgical intervention orfrom dental or periodontal disease. Bone healing includes, but is notlimited to, repair of bone deficits, such as those occurring in, e.g.,closed, open and non-union fractures. A cartilage defect is a damagedcartilage, less cartilage than desired, or cartilage that is less intactand coherent than desired. In the present invention, the p38 MAP kinaseinhibitors can be used for treating cartilage defects.

[0052] Included in conditions which present with low bone mass are, butnot limited to, primary and secondary osteoporosis, periodontal disease,alveolar bone loss, osteotomy bone loss, and childhood idiopathic boneloss. Conditions which present with low bone mass also includes, but arenot limited to, long term complications of osteoporosis such ascurvature of the spine, loss of height and prosthetic surgery.

[0053] The p38 MAP kinase inhibitors can be used to elevate peak bonemass in pre-menopausal women, to treat growth deficiencies, increasebone formation during distraction osteogenesis, and treat other skeletaldisorders, such as age-related osteoporosis, post-menopausalosteoporosis, glucocorticoid-induced osteoporosis or disuse osteoporosisand arthritis. The p38 MAP kinase inhibitors can also be useful inrepair of congenital, trauma-induced or surgical resection of bone (forinstance, for cancer treatment), and in cosmetic surgery.

[0054] Osteoporosis or porous bone is a disease characterized by netloss of bone mass per unit volume. The consequence of this loss of bonemass and resulting bone fracture is the failure of the skeleton toprovide adequate structural support for the body, low bone mass andstructural deterioration of bone tissue, leading to bone fragility andan increased susceptibility to fractures of the hip, spine, and wrist.Bone loss occurs without symptoms. Osteoporosis includes “secondaryosteoporosis,” such as glucocorticoid-induced osteoporosis,hyperthyroidism-induced osteoporosis, immobilization-inducedosteoporosis, heparin-induced osteoporosis or immunosuppressive-inducedosteoporosis. In people with osteoporosis, the bones can become so weakthat a sudden strain can cause a fracture or a vertebra to collapse.Most current osteoporosis treatments stop continued bone loss but do notenhance bone formation and thus bone quality remains poor but does notget worse.

[0055] Thus, the invention is also directed to a method of increasingbone mass in a mammal by administering a pharmaceutically effectiveamount of a p38 MAP kinase inhibitor to a mammal in need of increasedbone mass. The invention is also directed to a method of decreasing boneresorption in a patient by administering a pharmaceutically effectiveamount of a p38 MAP kinase inhibitor to a patient in need of decreasedbone resorption, thereby increasing bone mass to offset the decreasedbone resorption.

[0056] The invention is also directed to a method of increasing orenhancing the rate of bone growth in a mammal by administering apharmaceutically effective amount of a p38 MAP kinase inhibitor to amammal in need of increased or enhanced rate of bone growth.

[0057] The invention is further directed to a method of decreasingosteoclast differentiation by administering a pharmaceutically effectiveamount of a p38 MAP kinase inhibitor to a mammal in need of increasedosteoclast activity. As is known in the art, osteoclasts differentiationis mediated by p38 MAP kinase activity (Li et al., Endocrinology143:3105 (2002); Lee et al., Bone 30(1):71 (2002); Matsumoto et al.,FEBS Lett. 486:23 (2000); and Matsumoto et al., J. Biol. Chem. 275:31155(2000)).

[0058] The invention is also directed to a method of increasingchondrocyte differentiation in a mammal by administering apharmaceutically effective amount of a p38 MAP kinase inhibitor to amammal in need of increased chondrocyte differentiation. Chondrocytesare mature cartilage cells embedded in a lacuna within the cartilagematrix. Chondrocytes are formed embryologically through condensation anddifferentiation of mesenchymal cell precursors. After birth,chondrocytes are present in a variety of cartilaginous tissues. Duringbone healing, mesenchymal stem cells migrate and/or proliferate at thefracture site and begin to differentiate into chondrocytes. Chondrocytesat the osteoblast-chondrocyte boundary terminally differentiate intohypertrophic chondrocytes, express Type X collagen, secrete angiogenicfactors, and mineralize the cartilaginous matrix (calcified cartilage).The p38 kinase inhibitor can promote chondrocyte differentiation eitherindirectly by promoting proliferation and/or migration of mesenchymalstem cells, or by directly accelerating calcified cartilage formation,which is the end stage of chondrocyte differentiation.

[0059] In the invention, the p38 MAP kinase inhibitors can beadministered to a mammal to induce differentiation of bone-forming cellprecursors. By a “cell precursor” is intended a cell that possesses andretains the capacity for proliferation and differentiation, e.g.,mesenchymal cell, preosteoblast, and chondrocyte.

[0060] The invention is also directed to a method of increasing oraccelerating the rate of calcified cartilage formation in a mammal byadministering a pharmaceutically effective amount of a p38 MAP kinaseinhibitor to a mammal in need of accelerated calcified cartilageformation.

[0061] Veterinary uses of the p38 MAP kinase inhibitors are alsocontemplated. Such uses would include treatment of bone or cartilagedeficits or defects in domestic animals, livestock and thoroughbredhorses.

[0062] In the methods of the invention, a pharmaceutically effectiveamount of a p38 MAP kinase inhibitor and estrogen, a selective estrogenreceptor modulator, or a bisphosphonate can be administered whenappropriate as can be determined by those of skill in the art.

[0063] Preferred bisphosphonates include, but are not limited to,tiludronic acid, alendronic acid, zoledronic acid, ibandronic acid,risedronic acid, etidronic acid, clodronic acid, and pamidronic acid andtheir pharmaceutically acceptable salts. One skilled in the art willknow that these compounds are often referred to as their ion form, e.g.,tiludronate, alendronate, zoledronate, ibandronate, risedronate,etidronate, clodronate and pamidronate. Especially preferredbisphosphonates include alendronate and risedronate.

[0064] Inhibitors of p38 MAP Kinase

[0065] As used herein, the term “inhibitor” includes, but is not limitedto, any suitable molecule, compound, protein or fragment thereof,nucleic acid, formulation or substance that can regulate p38 MAP kinaseactivity. The inhibitor can affect a single p38 MAP kinase isoform(p38α, p38β, p3γ, and p38δ), more than one isoform, or all isoforms ofp38 MAP kinase. In a preferred embodiment, the inhibitor regulates the aisoform of p38 MAP kinase.

[0066] According to the present invention, it is contemplated that theinhibitor can exhibit its regulatory effect upstream or downstream ofp38 MAP kinase or on p38 MAP kinase directly. Examples of inhibitorregulated p38 MAP kinase activity include those where the inhibitor candecrease transcription and/or translation of p38 MAP kinase, candecrease or inhibit post-translational modification and/or cellulartrafficking of p38 MAP kinase, or can shorten the half-life of p38 MAPkinase. The inhibitor can also reversibly or irreversibly bind p38 MAPkinase, inactivate its enzymatic activity, or otherwise interfere withits interaction with downstream substrates.

[0067] If acting on p38 MAP kinase directly, in one embodiment theinhibitor should exhibit an IC₅₀ value of about 5 μM or less, preferably500 nm or less, more preferably 100 nm or less. In a related embodiment,the inhibitor should exhibit an IC₅₀ value relative to the p38α MAPkinase isoform that is about ten fold less than that observed when thesame inhibitor is tested against other p38 MAP kinase isoforms in acomparable assay.

[0068] Those skilled in the art can determine whether or not a compoundis useful in the present invention by evaluating its p38 MAP kinaseactivity as well as its relative IC₅₀ value. This evaluation can beaccomplished through conventional in vitro assays. In vitro assaysinclude assays that assess inhibition of kinase or ATPase activity ofactivated p38 MAP kinase. In vitro assays can also assess the ability ofthe inhibitor to bind p38 MAP kinase or to reduce or block an identifieddownstream effect of activated p38 MAP kinase, e.g., cytokine secretion.IC₅₀ values are calculated using the concentration of inhibitor thatcauses a 50% decrease as compared to a control.

[0069] A binding assay is a fairly inexpensive and simple in vitro assayto run. As previously mentioned, binding of a molecule to p38 MAPkinase, in and of itself, can be inhibitory, due to steric, allostericor charge-charge interactions. A binding assay can be performed insolution or on a solid phase using p38 MAP kinase or a fragment thereofas a target. By using this as an initial screen, one can evaluatelibraries of compounds for potential p38 MAP kinase regulatory activity.

[0070] The target in a binding assay can be either free in solution,fixed to a support, or expressed in or on the surface of a cell. A label(e.g., radioactive, fluorescent, quenching, etc.) can be placed on thetarget, compound, or both to determine the presence or absence ofbinding. This approach can also be used to conduct a competitive bindingassay to assess the inhibition of binding of a target to a natural orartificial substrate or binding partner. In any case, one can measure,either directly or indirectly, the amount of free label versus boundlabel to determine binding. There are many known variations andadaptations of this approach to minimize interference with bindingactivity and optimize signal.

[0071] For purposes of in vitro cellular assays, the compounds thatrepresent potential inhibitors of p38 MAP kinase function can beadministered to a cell in any number of ways. Preferably, the compoundor composition can be added to the medium in which the cell is growing,such as tissue culture medium for cells grown in culture. The compoundis provided in standard serial dilutions or in an amount determined byanalogy to known modulators. Alternatively, the potential inhibitor canbe encoded by a nucleic acid that is introduced into the cell whereinthe cell produces the potential inhibitor itself.

[0072] Alternative assays involving in vitro analysis of potentialinhibitors include those where cells (e.g., HeLa) transfected with DNAcoding for relevant kinases can be activated with substances such assorbitol, IL-1, TNF, or PMA. After immunoprecipitation of cell lysates,equal aliquots of immune complexes of the kinases are pre-incubated foran adequate time with a specific concentration of the potentialinhibitor followed by addition of kinase substrate buffer mix containinglabeled ATP and GST-ATF2 or MBP. After incubation, kinase reactions areterminated by the addition of SDS loading buffer. Phosphorylatedsubstrate is resolved through SDS-PAGE and visualized and quantitated ina phosphorimager. The p38 MAP kinase regulation, in terms ofphosphorylation and IC₅₀ values, can be determined by quantitation. Seee.g., Kumar, S. et al., Biochem. Biophys. Res. Commun. 235:533-538(1997).

[0073] Other in vitro assays can also assess the production of TNF-α asa correlation to p38 MAP kinase activity. One such example is a HumanWhole Blood Assay. In this assay, venous blood is collected from, e.g.,healthy male volunteers into a heparinized syringe and is used within 2hours of collection. Test compounds are dissolved in 100% DMSO and 1 μlaliquots of drug concentrations ranging from 0 to 1 mM are dispensedinto quadruplicate wells of a 24-well microtiter plate (Nunclon DeltaSI, Applied Scientific Co., San Francisco, Calif.). Whole blood is addedat a volume of 1 ml/well and the mixture is incubated for 15 minuteswith constant shaking (Titer Plate Shaker, Lab-Line Instruments, Inc.,Melrose Park, Ill.) at a humidified atmosphere of 5% CO₂ at 37° C. Wholeblood is cultured either undiluted or at a final dilution of 1:10 withRPMI 1640 (Gibco 31800+NaHCO₃, Life Technologies, Rockville, Md. andScios, Inc., Sunnyvale, Calif.). At the end of the incubation period, 10μl of LPS (E. coli 0111:B4, Sigma Chemical Co., St. Louis, Mo.) is addedto each well to a final concentration of 1 or 0.1 μg/ml for undiluted or1:10 diluted whole blood, respectively. The incubation is continued foran additional 2 hours. The reaction is stopped by placing the microtiterplates in an ice bath, and plasma or cell-free supernates are collectedby centrifugation at 3000 rpm for 10 minutes at 4° C. The plasma samplesare stored at −80° C. until assayed for TNF-α levels by ELISA, followingthe directions supplied by Quantikine Human TNF-α assay kit (R&DSystems, Minneapolis, Minn.). IC₅₀ values are calculated using theconcentration of inhibitor that causes a 50% decrease as compared to acontrol.

[0074] A similar assay is an Enriched Mononuclear Cell Assay. Theenriched mononuclear cell assay begins with cryopreserved HumanPeripheral Blood Mononuclear Cells (HPBMCs) (Clonetics Corp.) that arerinsed and resuspended in a warm mixture of cell growth media. Theresuspended cells are then counted and seeded at 1×10⁶ cells/well in a24-well microtitre plate. The plates are then placed in an incubator foran hour to allow the cells to settle in each well. After the cells havesettled, the media is aspirated and new media containing 100 ng/ml ofthe cytokine stimulatory factor Lipopolysaccharide (LPS) and a testchemical compound is added to each well of the microtiter plate. Thus,each well contains HPBMCs, LPS and a test chemical compound. The cellsare then incubated for 2 hours, and the amount of the cytokine TumorNecrosis Factor Alpha (TNF-α) is measured using an Enzyme LinkedImmunoassay (ELISA). One such ELISA for detecting the levels of TNF-α iscommercially available from R&D Systems. The amount of TNF-α productionby the HPBMCs in each well is then compared to a control well todetermine whether the chemical compound acts as an inhibitor of cytokineproduction.

[0075] Compounds useful in the practice of the present inventioninclude, but are not limited to, compounds of formula:

[0076] wherein

[0077] R₁ is a heteroaryl ring selected from 4-pyridyl, pyrimidinyl,quinolyl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl,1-benzimidazolyl, 4-pyridazinyl, and a 1,2,4-triazin-5-yl ring, whichheteroaryl ring is substituted one to three times with Y,N(R₁₀)C(O)R_(b), a halo-substituted mono- or di-C₁₋₆ alkyl-substitutedamino, or NHR_(a) and which ring is further optionally substituted withC₁₋₄ alkyl, halogen, hydroxyl, optionally-substituted C₁₋₄ alkoxy,optionally-substituted C₁₋₄ alkylthio, optionally-substituted Ca₄alkylsulfinyl, CH₂OR₁₂, amino, mono- and di-C₁₋₆ alkyl-substitutedamino, NHR_(a), N(R₁₀)C(O)R_(b), N(R₁₀)S(O)₂R_(d), or an N-heterocyclylring which has from 5 to 7 members and optionally contains an additionalheteroatom selected from oxygen, sulfur or NR₁₅;

[0078] Y is X₁—R_(a);

[0079] X₁ is oxygen or sulfur;

[0080] R_(a) is C₁₋₆ alkyl, aryl, arylC₁₋₆ alkyl, heterocyclic,heterocyclylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl, whereineach of these moieties can be optionally substituted;

[0081] R_(b) is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, orheterocyclylC₁₋₄ alkyl;

[0082] R_(d) is C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl,heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, or heterocyclylC₁₋₄alkyl;

[0083] R₃ is hydrogen;

[0084] R₄ is phenyl, naphth-1-yl, naphth-2-yl, or a heteroaryl, which isoptionally substituted by one or two substituents, each of which isindependently selected, and which, for a 4-phenyl, 4-naphth-1-yl,5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro,—C(Z)NR₇R₁₇, —C(Z)OR₁₆, —(CR₁₀R₂₀)_(v)COR₁₂, —SR₅, —SOR₅, —OR₁₂,halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl, -ZC(Z)R₁₂, —NR₁₀C(Z)R₁₆, or—(CR₁₀R₂₀)_(v)NR₁₀R₂₀ and which, for other positions of substitution, ishalogen, cyano, —C(Z)NR₁₃R₁₄, —C(Z)OR_(f), —(CR₁₀R₂₀)_(m″)COR_(f),—S(O)_(m)R_(f), —OR_(f), —OR₁₂, halo-substituted C₁₋₄ alkyl, C₁₋₄ alkyl,—(CR₁₀R₂₀)_(m″)NR₁₀C(Z)R_(f), —NR₁₀S(O)_(m′)R₈, —NR₁₀S(O)_(m′)NR₇R₁₇,-ZC(Z)R_(f), -ZC(Z)R₁₂, or —CR₁₀R₂₀)_(m″)NR₁₃R₁₄;

[0085] R_(f) is heterocyclyl, heterocyclylC₁₋₁₀ alkyl or R₈;

[0086] Z is oxygen or sulfur;

[0087] v is 0, 1, or 2;

[0088] m is 0, 1, or 2;

[0089] m′ is 1 or 2;

[0090] m″ is 0, 1, 2, 3, 4, or 5;

[0091] R₂ is C₁₋₁₀ alkyl N₃, —(CR₁₀R₂₀)_(n′)OR₉, heterocylyl,heterocycylC₁₋₁₀ alkyl, C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl,

[0092] C₃₋₇ cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl,C₅₋₇cycloalkenylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,heteroarylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₁₁, (CR₁₀R₂₀)_(n)S(O)_(m)R₁₈,(CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, (CR₁₀R₂₀)_(n)NR₁₃R)₁₄, (CR₁₀R₂₀)_(n)NO₂,(CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n′)SO₂R₁₈, (CR₁₀R₂₀)_(n)S(O)_(m′)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)C(Z)R₁₁, (CR₁₀R₂₀)_(n)OC(Z)R₁₁, (CR₁₀R₂₀)_(n)C(Z)OR₁₁,(CR₁₀R₂₀)_(n)C(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)C(Z)NR₁₀R₉,(CR₁₀R₂₀)_(n)NR₁₀C(Z)R₁₁, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)N(OR₆)C(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)N(OR₆)C(Z)R₁₁,(CR₁₀R₂₀)_(n)C(═NOR₆)R₁₁, (CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₉)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)OC(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₁₀, 5-(R₁₈)-1,2,4-oxadiazol-3-yl or4-(R₁₂)-5-(R₁₈R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl,arylalkyl, heteroaryl, heteroaryl alkyl, cycloalkyl, cycloalkyl alkyl,heterocyclic and heterocyclic alkyl groups can be optionallysubstituted;

[0093] n is an integer having a value of 1 to 10;

[0094] n′ is 0, or an integer having a value of 1 to 10;

[0095] R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR₇R₁₇,excluding the moieties —SR₅ being —SNR₇R₁₇ and —S(O)R₅ being —SOH;

[0096] R₆ is hydrogen, a pharmaceutically-acceptable cation, C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,heteroarylC₁₋₁₀ alkyl, heterocyclyl, aroyl, or C₁₋₁₀ alkanoyl;

[0097] R₇ and R₁₇ are each independently selected from hydrogen or C₁₋₄alkyl, or R₇ and R₁₇ together with the nitrogen to which they areattached form a heterocyclic ring of 5 to 7 members which ringoptionally contains an additional heteroatom selected from oxygen,sulfur or NR₁₅;

[0098] R₈ is C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₁₁,(CR₁₀R₂₀)_(n)S(O)_(m)R₁₈, (CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, or(CR₁₀R₂₀)_(n)NR₁₃R₁₄, wherein the aryl, arylalkyl, heteroaryl, andheteroaryl alkyl can be optionally substituted;

[0099] R₉ is hydrogen, —C(Z)R₁₁, optionally-substituted C₁₋₁₀ alkyl,S(O)₂R₁₈, optionally-substituted aryl or optionally-substituted arylC₁₋₄alkyl;

[0100] R₁₀ and R₂₀ are each independently selected from hydrogen or C₁₋₄alkyl;

[0101] R₁₁ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl;

[0102] R₁₂ is hydrogen or R₁₆;

[0103] R₁₃ and R₁₄ are each independently selected from hydrogen oroptionally-substituted C₁₋₄ alkyl, optionally-substituted aryl oroptionally-substituted arylC₁₋₄ alkyl, or together with the nitrogen towhich they are attached form a heterocyclic ring of 5 to 7 members whichring optionally contains an additional heteroatom selected from oxygen,sulfur or NR₉;

[0104] R₁₅ is R₁₀ or C(Z)C₁₋₄ alkyl;

[0105] R₁₆ is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, or C₃₋₇cycloalkyl;

[0106] R₁₈ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl,arylC₁₋₁₀ alkyl, heterocyclyl, heterocyclylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl; and R₁₉ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇cycloalkyl or aryl;

[0107] or a pharmaceutically-acceptable salt thereof,

[0108] or wherein

[0109] R₁, Y, X₁, R_(a), R_(b), R_(d), V, m, m′, m, Z, n, n′, and R₅ aredefined as above, and

[0110] R₂ is hydrogen, C₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₁₀ alkyl,C₅₋₇ cycloalkenyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀alkyl, heterocyclyl, heterocyclylC₁₋₁₀ alkyl, (CR₁₀R₂₈)_(n)OR₁₂,(CR₁₀R₂₈)_(n′)OR₁₃, (CR₁₀R₂₈)_(n′)S(O)_(m)R₂₅, (CR₁₀R₂₈)_(n)S(O)₂R₂₅,(CR₁₀R₂₈)_(n′)NHS(O)₂R₂₅, (CR₁₀R₂₈)_(n′)NR₈R₉, (CR₁₀R₂₈)_(n′)NO₂,(CR₁₀R₂₈)_(n′)CN, (CR₁₀R₂₈)_(n′)S(O)_(m)NR₈R₉, (CR₁₀R₂₈)_(n′)C(Z)R₁₃,(CR₁₀R₂₈)_(n′)C(Z)OR₁₃, (CR₁₀R₂₈)_(n′)OC(Z)NR₈R₉,(CR₁OR₂₈)_(n′)C(Z)NR₁₃OR₁₂, (CR₁₀R₂₈)_(n′)NR₁₀C(Z)R₁₃,(CR₁₀R₂₈)_(n′)NR₁₀C(Z)NR₈R₉, (CR₁₀R₂₈)_(n′)N(OR₂₁)C(Z)NR₈R₉,(CR₁₀R₂₈)_(n′)N(OR₂₁)C(Z)R₁₃, (CR₁₀R₂₈)_(n′)C(═NOR₂₁)R₁₃,(CR₁₀R₂₈)_(n′)NR₁₀C(═NR₂₇)NR₈R₉, (CR₁₀R₂₈)_(n′)OC(Z)NR₈R₉,(CR₁₀R₂₈)_(n′)NR₁₀C(Z)OR₁₀, (CR₁₀R₂₈)_(n′)NR₁₀C(Z)OR₁₀,5-(R₂₅)-1,2,4-oxadiazol-3-yl or4-(R₁₂)-5-(R₁₈R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein thecycloalkyl, cycloalkyl alkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, or heterocyclylalkyl moieties can beoptionally substituted;

[0111] R₃ is hydrogen or Q-(Y₁)_(t);

[0112] Q is an aryl or heteroaryl group;

[0113] t is 1, 2, or 3;

[0114] Y₁ is independently selected from hydrogen, C₁₋₅ alkyl,halo-substituted C₁₋₅ alkyl, halogen, or —(CR₁₀R₂₀)_(n)Y₂;

[0115] Y₂ is OR₈, NO₂, S(O)_(m″)R₁₁, SR₈, S(O)_(m″)OR₈, S(O)_(m)NR₈R₉,NR₈R₉, O(CR₁₀R₂₀)_(n′)NR₈R₉, C(O)R₈, CO₂R₈, CO₂(CR₁₀R₂₀)_(n′)CONR₈R₉,ZC(O)R₈, CN, C(Z)NR₈R₉, NR₁₀C(Z)R₈, C(Z)NR₈OR₉, NR₁₀C(Z)NR₈R₉,NR₁₀S(O)_(m)R₁₁, N(OR₂₁)C(Z)NR₈R₉, N(OR₂₁)C(Z)R₈, C(═NOR₂₁)R₈,NR₁₀C(═NR₁₅)SR₁₁, NR₁₀C(═NR₁₅)NR₈R₉, NR₁₀C(═CR₁₄R₂₄)SR₁₁,NR₁₀C(═CR₁₄R₂₄)NR₈R₉, NR₁₀C(O)C(O)NR₈R₉, NR₁₀C(O)C(O)OR₁₀,C(═NR₁₃)NR₈R₉, C(═NOR₁₃)NR₈R₉, C(═NR₁₃)ZR₁₁, OC(Z)NR₈R₉,NR₁₀S(O)_(m″)CF₃, NR₁₀C(Z)OR₁₀, 5-(R₁₈)-1,2,4-oxadiazol-3-yl or4-(R₁₂)-5-(R₁₈R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl;

[0116] R₄ is phenyl, naphth-1-yl or naphth-2-yl which is optionallysubstituted by one or two substituents, each of which is independentlyselected, and which, for a 4-phenyl, 4-naphth-1-yl or 5-naphth-2-ylsubstituent, is halo, nitro, cyano, C(Z)NR₇R₁₇, C(Z)OR₂₃,(CR₁₀R₂₀)_(v)COR₃₆, SR₅, SOR₅, OR₃₆, halo-substituted-C₁₋₄ alkyl, C₁₋₄alkyl, ZC(Z)R₃₆, NR₁₀C(Z)R₂₃, or (CR₁₀R₂₀)_(v)NR₁₀R₂₀ and which, forother positions of substitution, is halo, nitro, cyano, C(Z)NR₁₆R₂₆,C(Z)OR₈, (CR₁₀R₂₀)_(m″)COR₈, S(O)_(m)R₈, OR₈, halo-substituted-C₁₋₄alkyl, C₁₋₄ alkyl, (CR₁₀R₂₀)_(m″)NR₁₀C(Z)R₈, NR₁₀S(O)_(m′)R₁₁,NR₁₀S(O)_(m)NR₇R₁₇, ZC(Z)R₈ or (CR₁₀R₂₀)_(m) NR₁₆R₂₆;

[0117] R₇ and R₁₇ are each independently selected from hydrogen or C₁₋₄alkyl, or R₇ and R₁₇ together with the nitrogen to which they areattached form a heterocyclic ring of 5 to 7 members, which ringoptionally contains an additional heteroatom selected from oxygen,sulfur or NR₂₂;

[0118] R₈ is hydrogen, heterocyclyl, heterocyclylalkyl or R₁₁;

[0119] R₉ is hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl, or R₈ and R₉ can together with the nitrogen to whichthey are attached form a heterocyclic ring of 5 to 7 members, which ringoptionally contains an additional heteroatom selected from oxygen,sulfur or NR₁₂;

[0120] R₁₀ and R₂₀ are each independently selected from hydrogen or C₁₋₄alkyl;

[0121] R₁₁ is C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylalkyl,heteroaryl or heteroarylalkyl;

[0122] R₁₂ is hydrogen, —C(Z)R₁₃ or optionally-substituted C₁₋₄ alkyl,optionally-substituted aryl, optionally-substituted arylC₁₋₄ alkyl, orS(O)₂R₂₅;

[0123] R₁₃ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl, wherein all of these moieties can be optionallysubstituted;

[0124] R₁₄ and R₂₄ are each independently selected from hydrogen, alkyl,nitro or cyano;

[0125] R₁₅ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or aryl;

[0126] R₁₆ and R₂₆ are each independently selected from hydrogen oroptionally-substituted C₁₋₄ alkyl, optionally-substituted aryl oroptionally-substituted arylC₁₋₄ alkyl, or together with the nitrogen towhich they are attached form a heterocyclic ring of 5 to 7 members,which ring optionally contains an additional heteroatom selected fromoxygen, sulfur or NR₁₂;

[0127] R₁₈ and R₁₉ are each independently selected from hydrogen, C₁₋₄alkyl, substituted alkyl, optionally-substituted aryl,optionally-substituted arylalkyl, or together denote an oxygen orsulfur;

[0128] R₂₁ is hydrogen, a pharmaceutically-acceptable cation, C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,heteroarylalkyl, heterocyclyl, aroyl, or C₁₋₁₀ alkanoyl;

[0129] R₂₂ is R₁₀ or C(Z)-C₁₋₄ alkyl;

[0130] R₂₃ is C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, or C₃₋₅cycloalkyl;

[0131] R₂₅ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl,arylalkyl, heterocyclyl, heterocyclylC₁₋₁₀ alkyl, heteroaryl orheteroarylalkyl;

[0132] R₂₇ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, or aryl;

[0133] R₂₈ is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄alkyl, heteroaryl, heteroarylC₁₋₄alkyl, heterocyclyl, orheterocyclylC₁₋₄ alkyl moiety, all of which can be optionallysubstituted; and

[0134] R₃₆ is hydrogen or R₂₃;

[0135] or a pharmaceutically acceptable salt thereof.

[0136] Exemplary compounds of this formula include:

[0137]1-[3-(4-morpholinyl)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0138] 1-(3-chloropropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0139] 1-(3-azidopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0140] 1-(3-aminopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0141]1-(3-methylsulfonamidopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0142]1-[3-(N-phenylmethyl)aminopropyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0143]1-[3-(N-phenylmethyl-N-methyl)aminopropyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0144]1-[3-(1-pyrrolidinyl)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0145]1-(3-diethylaminopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0146]1-[3-(1-piperidinyl)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0147]1-[3-(methylthio)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0148]1-[2-(4-morpholinyl)ethyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0149]1-[3-(4-morpholinyl)propyl]-4-(3-methylthiophenyl)-5-(4-pyridyl)imidazole;

[0150](+/−)-1-[3-(4-morpholinyl)propyl]-4-(3-methylsulfinylphenyl)-5-(4-pyridyl)imidazole;

[0151]1-[3-(N-methyl-N-benzyl)aminopropyl]-4-(3-methylthiophenyl)-5-(4-pyridyl)imidazole;

[0152]1-[3-(N-methyl-N-benzyl)aminopropyl]-4-(3-methylsulfinylphenyl)-5-(4-pyridyl)imidazole;

[0153]1-[4-(methylthio)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0154]1-[4-(methylsulfinyl)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0155]1-[3-(methylthio)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0156](+/−)-1-[3-(methylsulfinyl)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0157]1-[2-(methylthio)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0158]1-[2-(methylsulfinyl)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0159]1-[4-(4-morpholinyl)butyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0160] 1-cyclopropyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0161] 1-isopropyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0162] 1-cyclopropylmethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0163] 1-tert-butyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0164] 1-(2,2-diethoxyethyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0165] 1-formylmethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0166] 1-hydroxyiminylmethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0167] 1-cyanomethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0168]1-[3-(4-morpholinyl)propyl)-4-(4-fluorophenyl)-5-(2-methylpyrid-4-yl)imidazole;

[0169]4-(4-fluorophenyl)-1-[3-(4-morpholinyl)propyl]-5-(2-chloropyridin-4-yl)imidazole;

[0170]4-(4-fluorophenyl)-1-[3-(4-morpholinyl)propyl]-5-(2-amino-4-pyridinyl)imidazole;

[0171]1-(4-carboxymethyl)propyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0172] 1-(4-carboxypropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0173]1-(3-carboxymethyl)ethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0174] 1-(3-carboxy)ethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0175]1-(1-benzylpiperidin-4-yl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

[0176]5-(2-aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-[3-(4-morpholinyl)propyl]imidazole;

[0177]5-(2-aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(1-benzylpiperidin-4-yl)imidazole;

[0178]5-(2-aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(2-propyl)imidazole;

[0179]5-(2-aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(cyclopropylmethyl)imidazole;

[0180]5-(2-aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(1-carboxyethyl-4-piperidinyl)imidazole;

[0181]5-(2-aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole;

[0182] 1-methyl-4-phenyl-5-(4-pyridyl)imidazole;

[0183] 1-methyl-4-[3-(chlorophenyl)]-5-(4-pyridinyl)imidazole;

[0184] 1-methyl-4-(3-methylthiophenyl)-5-(4-pyridyl)imidazole;

[0185] (+/−)-1-methyl-4-(3-methylsulfinylphenyl)-5-(4-pyridyl)imidazole;

[0186](+/−)-4-(4-fluorophenyl)-1-[3-(methylsulfinyl)propyl]-5-(4-pyridinyl)imidazole;

[0187]4-(4-fluorophenyl)-1-[(3-methylsulfonyl)propyl]-5-(4-pyridinyl)imidazole;

[0188] 1-(3-phenoxypropyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;

[0189]1-[3-(phenylthio)propyl]-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;

[0190]1-[3-(4-morpholinyl)propyl]-4-(4-fluorophenyl)-5-(4-quinolyl)imidazole;

[0191](+/−)-1-(3-phenylsulfinylpropyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;

[0192] 1-(3-ethoxypropyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;

[0193]1-(3-phenylsulfonylpropyl-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;

[0194]1-[3-(4-morpholinyl)propyl]-4-(3-chlorophenyl)-5-(4-pyridyl)imidazole;

[0195]1-[3-(4-morpholinyl)propyl]-4-(3,4-dichlorophenyl)-5-(4-pyridyl)imidazole;

[0196]4-[4-(4-fluorophenyl)-1-[3-(4-morpholinyl)propyl]-5-(pyrimid-2-one-4-yl)imidazole;

[0197]4-(4-fluorophenyl)-5-[2-(methylthio)-4-pyrimidinyl]-1-[3-(4-morpholinyl)propyl]imidazole;

[0198](+/−)-4-(4-fluorophenyl)-5-[2-(methylsulfinyl)-4-pyrimidinyl]-1-[3-(4-morpholinyl)propyl]imidazole;

[0199] (E)-1-(1-propenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;

[0200] 1-(2-propenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;

[0201]5-[(2-N,N-dimethylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-[3-(4-morpholinyl)propyl]imidazole;

[0202]1-[3-(4-morpholinyl)propyl]-5-(4-pyridinyl)-4-[4-(trifluoromethyl)phenyl]imidazole;

[0203]1-[3-(4-morpholinyl)propyl]-5-(4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]imidazole;

[0204]1-(cyclopropylmethyl)-4-(3,4-dichlorophenyl)-5-(4-pyridinyl)imidazole;

[0205]1-(cyclopropylmethyl)-4-(3-trifluoromethylphenyl)-5-(4-pyridinyl)imidazole;

[0206]1-(cyclopropylmethyl)-4-(4-fluorophenyl)-5-(2-methylpyrid-4-yl)imidazole;

[0207]1-[3-(4-morpholinyl)propyl]-5-(4-pyridinyl)-4-(3,5-bistrifluoromethylphenyl)imidazole;

[0208]5-[4-(2-aminopyrimidinyl)]-4-(4-fluorophenyl)-1-(2-carboxy-2,2-dimethylethyl)imidazole;

[0209]1-(1-formyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;

[0210]5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(1-methyl-4-piperidinyl)imidazole;

[0211]1-(2,2-dimethyl-3-morpholin-4-yl)propyl-4-(4-fluorophenyl)-5-(2-amino-4-pyrimidinyl)imidazole;

[0212] 4-(4-fluorophenyl)-5-(4-pyridyl)-1-(2-acetoxyethyl)imidazole;

[0213]5-(2-aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(1-benzylpyrrolin-3-yl)imidazole;

[0214]5-(2-aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(2,2,6,6-tetramethylpiperidin-4-yl)imidazole;

[0215]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-N-methylpiperidine)imidazole;

[0216]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-N-morpholino-1-propyl)imidazole;

[0217]5-[4-(2-N-methylamino)pyrimidinyl)-4-(4-fluorophenyl)-1-(4-piperidine)imidazole;

[0218]5-[(2-ethylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperidin-4-yl)imidazole;

[0219]4-(4-fluorophenyl)-5-[2-(isopropyl)aminopyrimidin-4-yl]-1-(1-methylpiperidin-4-yl)imidazole;

[0220]5-(2-acetamido-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-N-morpholino-1-propyl)imidazole;

[0221]5-(2-acetamido-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(1-methyl-4-piperidinyl)imidazole;

[0222]5-[4-(2-N-methylthio)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-piperidine)imidazole;

[0223]4-(fluorophenyl)-1-(methyl-4-piperidinyl)-5-(2-methylthio-4-pyrimidinyl)imidazole;

[0224]4-(fluorophenyl)-1-(methyl-4-piperidinyl)-5-(2-methysulfinyl-4-pyrimidinyl)imidazole;

[0225]1-tert-butyl-4-(4-fluorophenyl)-5-(2-methysulfinyl-4-pyrimidinyl)imidazole;

[0226]5-[4-(2-aminopyrimidinyl)]-4-(4-fluorophenyl)-1-(2,2,6,6-tetramethyl-4-piperidinyl)imidazole;

[0227]5-[4-(2-N-methylamino-4-pyrimidinyl)]-4-(4-fluorophenyl)-1-(2,2,6,6-tetramethyl-4-piperidine)imidazole;

[0228]5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(tetrahydro-4-thiopyranyl)imidazole;

[0229]5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(tetrahydro-4-pyranyl)imidazole;

[0230]5-(2-methylamino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(2-cyanoethyl)imidazole;

[0231]5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(tetrahydro-4-sulfinylpyranyl)imidazole;

[0232]5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(tetrahydro-4-sulfonylpyranyl)imidazole;

[0233]5-(2-methylamino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl-4-piperidinyl)imidazole;

[0234]5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(trifluoroacetyl-4-piperidinyl)imidazole;

[0235] 5-(4-pyridyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole;

[0236]5-(4-pyridyl)-4-(4-fluorophenyl)-1-(1-t-butoxycarbonyl-4-piperidinyl)imidazole;

[0237]5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-(1,3-dioxycyclopentyl)cyclohexyl)imidazole;

[0238]5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-ketocyclohexyl)imidazole;

[0239] 5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-cyclohexyloxime) imidazole;

[0240] 5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-cyclohexylhydroxylamine) imidazole;

[0241]5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(trans-4-hydroxyurea)imidazole;

[0242]5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(cis-4-hydroxyurea)imidazole;

[0243]5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-hydroxycyclohexyl)imidazole;

[0244]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-ketocyclohexyl)imidazole;

[0245]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(trans-4-hydroxycyclohexyl)imidazole;

[0246]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(cis-4-hydroxycyclohexyl)imidazole;

[0247]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-[4-(cis-pyrrolidinyl)cyclohexyl]imidazole;

[0248]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-[4-(trans-1-pyrrolidinyl)cyclohexyl]imidazole;

[0249]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-ethynyl-4-hydroxycyclohexyl)imidazole;

[0250]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-(1-propynyl)-4-hydroxycyclohexyl)imidazole;

[0251]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-amino-4-methylcyclohexyl)imidazole;

[0252]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-acetamido-4-methylcyclohexyl)imidazole;

[0253]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-methylcyclohexyl)imidazole;

[0254]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-oxiranylcyclohexyl)imidazole;

[0255]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-cyanomethyl-4-hydroxycyclohexyl)imidazole;

[0256]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-hydroxymethylcyclohexyl)imidazole;

[0257]5-[4-(2-amino)pyrimidinyl]-4-(4-fluorophenyl)-1-[4-hydroxy-4-(1-propynyl)-cyclohexyl]imidazole;

[0258]5-[4-(2-amino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-methylcyclohexyl)imidazole;

[0259]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-isopropyl-cyclohexyl)imidazole;

[0260]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-phenyl-cyclohexyl)imidazole;

[0261]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-benzyl-cyclohexyl)imidazole;

[0262]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-cyanomethylcyclohexyl)imidazole;

[0263]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-(2-cyanoethyl)cyclohexyl)imidazole;

[0264]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-(2-aminoethyl)cyclohexyl)imidazole;

[0265]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-(2-nitroethyl)-cyclohexyl)imidazole;

[0266]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxymethyl-4-aminocyclohexyl)imidazole;

[0267]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-aminocyclohexyl)imidazole;

[0268]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-aminocyclohexyl)imidazole;

[0269]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-thiomethylcyclohexyl)imidazole;

[0270]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-hydroxymethylcyclohexyl)imidazole;

[0271]5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-aminomethylcyclohexyl)imidazole;

[0272]5-[4-(2-amino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-amino-4-methylcyclohexyl)imidazole;

[0273]5-[4-(2-amino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-methylcyclohexyl)imidazole;

[0274]5-[4-(2-amino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-oxiranylcyclohexyl)imidazole;

[0275]4-(fluorophenyl)-1-(methyl-4-piperidinyl)-5-(2-methysulfinyl-4-pyrimidinyl)imidazole;

[0276]4-(fluorophenyl)-1-(methyl-4-piperidinyl)-5-(2-methylthio-4-pyrimidinyl)imidazole;

[0277]5-[(2-benzylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperidin-4-yl)imidazole;

[0278]4-(4-fluorophenyl)-1-(1-methylpiperidin-4-yl)-5-[2-(4-tetrahydrothiopyranyl)aminopyrimidin-4-yl]imidazole;

[0279]4-(4-fluorophenyl)-5-[(2-hydroxy)ethylamino]pyrimidin-4-yl-1-(1-methylpiperidin-4-yl)imidazole;

[0280]5-[(2-(3-chlorobenzylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperidin-4-yl)imidazole;

[0281]5-[(2-(1-naphthylmethylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperidin-4-yl)imidazole;

[0282]5-[(2-(1-benzyl-4-piperidinylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperidin-4-yl)imidazole;

[0283]4-(4-fluorophenyl)-1-(1-methylpiperidin-4-yl)-5-[2-[3-(morpholino)propyl]aminopyrimidin-4-yl]imidazole;

[0284]5-[2-[(3-bromophenyl)amino]pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperidin-4-yl)imidazole;

[0285]5-[(2-(piperonylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperidin-4-yl)imidazole;

[0286]5-[(2-(4-piperidinylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperidin-4-yl)imidazole;

[0287]5-[(2-(5-chlorotryptamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperidin-4-yl)imidazole;

[0288]5-[(2-(2,2,6,6-tetramethylpiperidin-4-yl)aminopyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperidin-4-yl)imidazole;

[0289]5-[(2-[1-ethoxycarbonyl)piperidin-4-yl]aminopyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperidin-4-yl)imidazole;

[0290]1-(4-oxocyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl]imidazole;

[0291]cis-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl]imidazole;

[0292]trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl]imidazole;

[0293]1-(4-oxocyclohexyl)-4-(4-fluorophenyl)-5-[(2-methylthio)pyrimidin-4-yl]imidazole;

[0294]trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2methylthio)pyrimidin-4-yl]imidazole;

[0295]1-(4-oxocyclohexyl)-4-(4-fluorophenyl)-5-[(2-hydroxy)pyrimidin-4-yl]imidazole;

[0296]1-(4-oxocyclohexyl)-4-(4-fluorophenyl)-5-[(2-isopropoxy)pyrimidin-4-yl]imidazole;

[0297]1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-isopropoxy)pyrimidin-4-yl]imidazole;

[0298]trans-1-(4-hydroxy-4-methylcyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl]imidazole;

[0299]cis-1-(4-hydroxy-4-methylcyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl]imidazole;

[0300]trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-ethoxy)pyrimidin-4-yl]imidazole;

[0301]1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)imidazole;

[0302]1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-phenoxy-4-pyridinyl)imidazole;

[0303]1-(4-piperidinyl)-4-(4-fluorophenyl)-5-[2-(4-methoxyphenoxy)-4-pyridinyl]imidazole;

[0304]1-(4-piperidinyl)-4-(4-fluorophenyl)-5-[2-(4-fluorophenoxy)-4-pyridinyl]imidazole;

[0305]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-methoxyphenoxy)pyrimidin-4-yl]imidazole;

[0306]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-fluorophenoxy)pyrimidin-4-yl]imidazole;

[0307]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-aminocarbonylphenoxy)pyrimidin-4-yl]imidazole;

[0308]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-ethylphenoxy)pyrimidin-4-yl]imidazole;

[0309]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-benzyloxyphenoxy)pyrimidin-4-yl]imidazole;

[0310]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-cyanophenoxy)pyrimidin-4-yl]imidazole;

[0311]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-hydroxyphenoxy)pyrimidin-4-yl]imidazole;

[0312]1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[2-(phenoxy)pyrimidin-4-yl]imidazole;

[0313]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(2,6-dimethylphenoxy)pyridin-4-yl]imidazole;

[0314]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-methylphenoxy)pyridin-4-yl]imidazole;

[0315]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-chlorophenoxy)pyridin-4-yl]imidazole;

[0316]1-[3-(N-morpholino)propyl]-4-(4-fluorophenyl)-5-[2-(phenoxy)pyrimidin-4-yl]imidazole;

[0317]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(3-methoxyphenoxy)pyrimidin-4-yl]imidazole;

[0318]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-phenylphenoxy)pyrimidin-4-yl]imidazole;

[0319]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-phenoxyphenoxy)pyrimidin-4-yl]imidazole;

[0320]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(3-hydroxyphenoxy)pyrimidin-4-yl]imidazole;

[0321]1-(3-(N-morpholino)propyl)-4-(4-fluorophenyl)-5-[2-(4-fluorophenoxy)pyrimidin-4-yl]imidazole;

[0322]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(2-hydroxyphenoxy)pyrimidin-4-yl]imidazole;

[0323]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-((3,4-methylenedioxy)phenoxy)pyrimidin-4-yl]imidazole;

[0324]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(3-fluorophenoxy)pyrimidin-4-yl]imidazole;

[0325]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(2-fluorophenoxy)pyrimidin-4-yl]imidazole;

[0326]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(2-methoxyphenoxy)pyrimidin-4-yl]imidazole;

[0327]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(3-trifluoromethylphenoxy)pyrimidin-4-yl]imidazole;

[0328]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(3,4-difluorophenoxy)pyrimidin-4-yl]imidazole;

[0329]1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-methylsulfonylphenoxy)pyrimidin-4-yl]imidazole;

[0330]1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-thiophenoxypyrimidin-4-yl)imidazole;

[0331]1-(4-piperidinyl)-4-(4-fluorophenyl)-5-[2-(1-methyltetrazol-5-ylthio)pyridin-4-yl]imidazole;

[0332]5-[2-(2-hydroxyethoxy)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(4-oxocyclohexyl)imidazole;

[0333]5-[2-(2-hydroxyethoxy)]pyrimidin-4-yl)-4-(4-fluorophenyl)-1-(4-hydroxycyclohexyl)imidazole;

[0334]5-[2-(2-tert-butylamino)ethoxypyrimidin-4-yl]-4-(4-fluorophenyl)-1-(4-oxocyclohexyl)imidazole;

[0335]5-[2-(2-tert-butylamino)ethoxypyrimidin-4-yl]-4-(4-fluorophenyl)-1-(4-hydroxycyclohexyl)imidazole;

[0336]1-(4-piperidinyl)-4-(4-Fluorophenyl)-5-(2-isopropoxy-4-pyrimidinyl)imidazole;

[0337]1-(4-piperidinyl)-4-(4-Fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)imidazole;

[0338]5-(2-hydroxy-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole;

[0339]5-(2-methoxy-4-pyridinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole;

[0340]5-(2-isopropoxy-4-pyridinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole;

[0341]5-(2-methylthio-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole;

[0342]5-(2-methylthio-4-pyrimidinyl)-4-(4-fluorophenyl)-1-[1-methyl-4-piperidinyl]imidazole;

[0343]5-(2-ethoxy-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole;

[0344]1-(1-ethylcarboxylpiperidin-4-yl)-3-(4-thiomethylphenyl)-5-[2-(thiomethyl)pyrimidin-4-yl]-imidazole;

[0345]1-(1-ethylcarbonylpiperidin-4-yl)-4-(4-methylsulfinylphenyl)-5-[(2-methylsulfinyl)pyrimidin-4-yl]imidazole;

[0346]2-(4-methylthiophenyl)-4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)imidazole;

[0347]2-(4-methylsulfinylphenyl)-4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)imidazole;

[0348]2-[(4-N,N-dimethyl)aminomethylphenyl]-4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)imidazole;

[0349]2-[(4-N,N-dimethyl)aminomethylphenyl]-4-(4-fluorophenyl)-5-(2-phenoxy-4-pyrimidinyl)imidazole;

[0350](+/−)-2-(4-methylsulfinylphenyl]-4-(4-fluorophenyl)-5-(2-phenoxy-4-pyrimidinyl)imidazole;

[0351]2-(4-methylthiophenyl]-4-(4-fluorophenyl)-5-(2-phenoxy-4-pyrimidinyl)imidazole;

[0352] and pharmaceutically acceptable salts thereof.

[0353] Compounds useful in the practice of the present invention alsoinclude, but are not limited to, compounds of formula:

[0354] wherein

[0355] R₁ is hydrogen, C₁₋₅ alkyl, halogen, C₁₋₅ alkoxy, or arylC₁₋₅alkyl;

[0356] R₂ and R₄ are independently hydrogen, C₁₋₅ alkyl, aryl, arylC₁₋₅alkyl, heteroaryl, heteroarylC₁₋₅ alkyl, heterocyclic, orheterocyclicC₁₋₅ alkyl; and

[0357] R₃ is hydrogen or C₁₋₃ alkyl;

[0358] or a pharmaceutically-acceptable salt thereof.

[0359] Compounds useful in the practice of the present invention alsoinclude, but are not limited to, compounds of formula:

[0360] wherein

[0361] X is O, CH₂, S or NH, or the moiety X—R¹ is hydrogen;

[0362] R¹ is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₆alkyl, heterocyclyl, heterocyclylC₁₋₆ alkyl, heteroaryl, orheteroarylC₁₋₆ alkyl, any of which, except for hydrogen, can beoptionally substituted;

[0363] V is CH or N;

[0364] Ar is an aryl or heteroaryl ring, either of which can beoptionally substituted;

[0365] one of X₁ and X₂ is N, and the other is NR¹⁵, wherein R¹⁵ ishydrogen, C₁₋₆ alkyl, or arylC₁₋₆ alkyl;

[0366] X₃ is a covalent bond or C(R²)(R³);

[0367] R² and R³ independently represent optionally substituted C₁₋₆alkyl, or R² and R³ together with the carbon atom to which they areattached form an optionally substituted C₃₋₇ cycloalkyl, C₃₋₇cycloalkenyl, or 5- to 7-membered heterocyclyl ring containing up tothree heteroatoms independently selected from N, O, and S;

[0368] n is 0, 1, 2, 3, or 4;

[0369] Y is NR¹⁰R¹¹, NR¹⁰C(Z)NR¹⁰R¹¹, NR¹⁰COOR¹¹, NR¹⁰SO₂R¹¹, orC(O)NR⁴R⁵;

[0370] R⁴ and R⁵ independently represent hydrogen, C₁₋₆ alkyl, C₃₋₇cycloalkyl, aryl, arylC₁₋₆ alkyl, heteroaryl, heteroarylC₁₋₆ alkyl,heterocyclyl, or heterocyclylC₁₋₆ alkyl, any one of which, excepthydrogen, can be optionally substituted, or R⁴ and R⁵ together with thenitrogen atom to which they are attached form a 4- to 10-memberedoptionally-substituted monocyclic or bicyclic ring;

[0371] R¹³ is hydrogen, X—R¹, halogen, optionally-substituted C₁₋₆alkylsulfinyl, CH₂OR¹⁴, di-C₁₋₆ alkylamino, N(R⁶)C(O)R⁷, N(R⁶)S(O)₂R⁸,or a 5- to 7-membered N-heterocyclyl ring which optionally contains anadditional heteroatom selected from O, S, and NR⁹;

[0372] R¹⁴ is hydrogen, —C(Z)R¹² or optionally-substituted C₁₋₆ alkyl,optionally-substituted aryl, optionally-substituted arylC₁₋₆ alkyl orS(O)₂R⁸;

[0373] R⁶ is hydrogen or C₁₋₆ alkyl;

[0374] R⁷ is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₆alkyl, heteroaryl, heteroarylC₁₋₆ alkyl, heterocyclyl orheterocyclylC₁₋₆ alkyl;

[0375] R⁸ is C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₆ alkyl,heteroaryl, heteroarylC₁₋₆ alkyl, heterocyclyl or heterocyclylC₁₋₆alkyl;

[0376] R⁹ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or aryl;

[0377] R¹⁰, R¹¹ and R¹² are independently selected from hydrogen, C₁₋₆alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclylC₁₋₆ alkyl,heterocyclylC₂₋₆ alkenyl, aryl, arylC₁₋₆ alkyl, arylC₂₋₆ alkenyl,heteroaryl, heteroarylC₁₋₆ alkyl and heteroarylC₂₋₆ alkenyl, any ofwhich can be optionally substituted; or NR¹⁰R¹¹ can represent a 5- to7-membered heterocyclyl ring optionally containing an additionalheteroatom selected from O, N and S; and

[0378] Z is oxygen or sulfur;

[0379] or a pharmaceutically-acceptable salt thereof.

[0380] Compounds useful in the practice of the present invention alsoinclude, but are not limited to, compounds of formulas:

[0381] wherein

[0382] R₁ is a heteroaryl selected from 4-pyridyl, 4-pyrimidinyl,4-quinolyl, 6-isoquinolinyl, quinazolin-4-yl, 1-imidazolyl,1-benzimidazolyl, 4-pyridazinyl, and a 1,2,4-triazin-5-yl ring, whichheteroaryl ring is substituted one to three times with Y, NHR_(a),optionally-substituted C₁₋₄ alkyl, halogen, hydroxyl,optionally-substituted C₁₋₄ alkoxy, optionally-substituted C₁₋₄alkylthio, optionally-substituted C₁₋₄ alkylsulfinyl, CH₂OR₁₂, amino,mono- and di-C₁₋₆ alkyl-substituted amino, N(R₁₀)C(O)R_(b),N(R₁₀)S(O)₂R_(d), or an N-heterocyclyl ring which has from 5 to 7members and optionally contains an additional heteroatom selected fromoxygen, sulfur or NR₁₅;

[0383] Y is X₁—R₁;

[0384] X₁ is oxygen or sulfur;

[0385] R_(a) is C₁₋₆ alkyl, aryl, arylC₁₋₆ alkyl, heterocyclic,heterocyclylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl, whereineach of these moieties can be optionally substituted;

[0386] R_(b) is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, orheterocyclylC₁₋₄ alkyl;

[0387] R_(d) is C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl,heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, or heterocyclylC₁₋₄alkyl;

[0388] R₄ is phenyl, naphth-1-yl, naphth-2-yl, a heteroaryl or a fusedphenyl-containing ring system, which is optionally substituted by one ortwo substituents, each of which is independently selected, and which,for a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-ylsubstituent, is halogen, cyano, nitro, —C(Z)NR₇R₁₇, —C(Z)OR₁₆,—(CR₁₀R₂₀)_(v)COR₁₂, —SR₅, —SOR₅, —OR₁₂, halo-substituted-C₁₋₄ alkyl,C₁₋₄ alkyl, -ZC(Z)R₁₂, —NR₁₀C(Z)R₁₆, or —(CR₁₀R₂₀)_(v)NR₁₀R₂₀ and which,for other positions of substitution, is halogen, cyano, nitro, phenyl,—C(Z)NR₁₃R₁₄, —C(Z)OR_(f), —(CR₁₀R₂₀)_(m″)COR_(f), —S(O)_(m)R_(f),—OR_(f), halo-substituted C₁₋₄ alkyl, C₁₋₁₀ alkyl, -ZC(Z)R_(f),optionally-substituted phenyl, —(CR₁₀R₂₀)_(m″)NR₁₀C(Z)R_(f),—NR₁₀S(O)_(m′)R₈, —NR₁₀S(O)_(m′)NR₇R₁₇, -ZC(Z)R₁₂, or—(CR₁₀R₂₀)_(m″)NR₁₃R₁₄;

[0389] R_(f) is heterocyclyl, heterocyclylC₁₁—O alkyl or R₈;

[0390] v is 0, 1, or 2;

[0391] m is 0, 1, or 2;

[0392] m′ is 1 or 2;

[0393] m″ is 0, 1, 2, 3, 4, or 5;

[0394] R₂ hydrogen, —(CR₁₀R₂₃)_(n)OR₉, heterocylyl, heterocyclylC₁₋₁₀alkyl, C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl,C₅₋₇cycloalkenylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,heteroarylC₁₋₁₀ alkyl, (CR₁₀R₂₃)_(n)OR₁₁, (CR₁₀R₂₃)_(n)S(O)_(m)R₁₈,(CR₁₀R₂₃)_(n)NHS(O)₂R₁₈, (CR₁₀R₂₃)_(n)NR₁₃R₁₄, (CR₁₀R₂₃)_(n)NO₂,(CR₁₀R₂₃)_(n)CN, (CR₁₀R₂₃)_(n)S(O)_(m′)NR₁₃R₁₄, (CR₁₀R₂₃)_(n)C(Z)R₁₁,(CR₁₀R₂₃)_(n)OC(Z)R₁₁, (CR₁₀R₂₃)_(n)C(Z)OR₁₁, (CR₁₀R₂₃)_(n)C(Z)NR₁₃R₁₄,(CR₁₀R₂₃)_(n)C(Z)NR₁₁R₉, (CR₁₀R₂₃)_(n)NR₁₀C(Z)R₁₁,(CR₁₀R₂₃)_(n)NR₁₀C(Z)NR₁₃R₁₄, (CR₁₀R₂₃)_(n)N(OR₆)C(Z)NR₁₃R₁₄,(CR₁₀R₂₃)_(n)N(OR₆)C(Z)R₁₁, (CR₁₀R₂₃)_(n)C(═NOR₆)R₁₁,(CR₁₀R₂₃)_(n)NR₁₀C(═NR₁₉)NR₁₃R₁₄, (CR₁₀R₂₃)_(n)OC(Z)NR₁₃R₁₄,(CR₁₀R₂₃)_(n)NR₁₀C(Z)NR₁₃R₁₄, (CR₁₀R₂₃)_(n)NR₁₀C(Z)OR₁₀,5-(R₁₈)-1,2,4-oxadiazol-3-yl or4-(R₁₂)-5-(R₁₈R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl,arylalkyl, heteroaryl, heteroaryl alkyl, cycloalkyl, cycloalkyl alkyl,heterocyclic and heterocyclic alkyl groups can be optionallysubstituted;

[0395] n is 0, or an integer having a value of 1 to 10;

[0396] Z is oxygen or sulfur;

[0397] R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR₇R₁₇,excluding the moieties —SR₅ being —SNR₇R₁₇ and —S(O)R₅ being —SOH;

[0398] R₆ is hydrogen, a pharmaceutically-acceptable cation, C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄alkyl, heterocyclyl, aroyl, or C₁₋₁₀ alkanoyl;

[0399] R₇ and R₁₇ are each independently selected from hydrogen or C₁₋₄alkyl, or R₇ and R₁₇ together with the nitrogen to which they areattached form a heterocyclic ring of 5 to 7 members which ringoptionally contains an additional heteroatom selected from oxygen,sulfur or NR₁₅;

[0400] R₈ is C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₁₁,(CR₁₀R₂₀)_(n)S(O)_(m)R₁₈, (CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, or(CR₁₀R₂₀)_(n)NR₁₃R₁₄, wherein the aryl, arylalkyl, heteroaryl, andheteroaryl alkyl can be optionally substituted;

[0401] R₉ is hydrogen, —C(Z)R₁₁, optionally-substituted C₁₋₁₀ alkyl,S(O)₂R₁₈, optionally-substituted aryl or optionally-substituted arylC₁₋₄alkyl;

[0402] R₁₀ and R₂₀ are each independently selected from hydrogen or C₁₋₄alkyl;

[0403] R₁₁ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl, wherein the aryl, arylalkyl, heteroaryl,heteroaryl alkyl, heterocyclyl or heterocyclylalkyl can be optionallysubstituted;

[0404] R₁₂ is hydrogen or R₁₆;

[0405] R₁₃ and R₁₄ are each independently selected from hydrogen oroptionally-substituted C₁₋₄ alkyl, optionally-substituted aryl oroptionally-substituted arylC₁₋₄ alkyl, or together with the nitrogen towhich they are attached form a heterocyclic ring of 5 to 7 members whichring optionally contains an additional heteroatom selected from oxygen,sulfur or NR₉;

[0406] R₁₅ is hydrogen, C₁₋₄ alkyl or C(Z)-C₁₋₄ alkyl;

[0407] R₁₆ is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, or C₃₋₇cycloalkyl;

[0408] R₁₈ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl,arylC₁₋₁₀ alkyl, heterocyclyl, heterocyclylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl, wherein the aryl, arylalkyl, heteroaryl,heteroaryl alkyl, heterocyclyl or heterocyclylalkyl can be optionallysubstituted;

[0409] R₁₉ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or aryl; and

[0410] R₂₃ is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, orheterocyclylC₁₋₄ alkyl, all of which can be optionally substituted;

[0411] or a pharmaceutically-acceptable salt thereof.

[0412] Exemplary compounds of these formulas include:

[0413] 4-[1-(4-fluorophenyl)-3-phenyl-1H-pyrazol-5-yl]pyridine

[0414] 4-[4-bromo-1-(4-fluorophenyl)-3-phenyl-1H-pyrazol-5-yl]pyridine

[0415]4-[1-(4-fluorophenyl)-3-[4-(methylthio)phenyl]-1H-pyrazol-5-yl]pyridine

[0416]4-[1-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl]pyridine4-[1-(4-fluorophenyl)-3-[4-(methylsulfinyl)phenyl]-1H-pyrazol-5-yl]pyridine;

[0417]4-[1-(4-fluorophenyl)-4,5-dihydro-3-phenyl-1H-pyrazol-5-yl]pyridine

[0418]4-[1-(4-fluorophenyl)-4,5-dihydro-3-[4-(methylthio)phenyl]-1H-pyrazol-5-yl]pyridine

[0419] and pharmaceutically acceptable salts thereof.

[0420] Compounds useful in the practice of the present invention alsoinclude, but are not limited to, compounds of formulas:

[0421] wherein

[0422] R₁ is 4-pyridyl or 4-pyrimidinyl ring, which ring is optionallysubstituted one or more times with Y, C₁₋₄ alkyl, halogen, hydroxyl,C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, CH₂OR₁₂, amino, mono-and di-C₁₋₆ alkyl-substituted amino, N(R₁₀)C(O)R_(b), or anN-heterocyclyl ring which has from 5 to 7 members and optionallycontains an additional heteroatom selected from oxygen, sulfur or NR₅;

[0423] Y is X₁—R_(a);

[0424] X₁ is oxygen, sulfur, or NH;

[0425] R_(a) is C₁₋₆ alkyl, aryl, arylC₁₋₆ alkyl, heterocyclic,heterocyclylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl, whereineach of these moieties can be optionally substituted;

[0426] R_(b) is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, orheterocyclylC₁₋₄ alkyl, wherein each of these moieties can be optionallysubstituted;

[0427] R₄ is phenyl, naphth-1-yl, naphth-2-yl, or a heteroaryl, which isoptionally substituted by one or two substituents, each of which isindependently selected, and which, for a 4-phenyl, 4-naphth-1-yl,5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro,—C(Z)NR₇R₁₇, —C(Z)OR₁₆, —(CR₁₀R₂₀)_(v)COR₁₂, —SR₅, —SOR₅, —OR₁₂,halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl, -ZC(Z)R₁₂, —NR₁₀C(Z)R₁₆, or—(CR₁₀R₂₀)_(v)NR₁₀R₂₀ and which, for other positions of substitution, ishalogen, cyano, —C(Z)NR₁₃R₁₄, —C(Z)OR_(f), —(CR₁₀R₂₀)_(m″)COR_(f),—S(O)_(m)R_(f), —OR_(f), halo-substituted C₁₋₄ alkyl, C₁₋₄ alkyl,-ZC(Z)R_(f), —(CR₁₀R₂₀)_(m″)NR₁₀C(Z)R_(f), —NR₁₀S(O)_(m)R₈,—NR₁₀S(O)_(m′)NR₇R₁₇, or —(CR₁₀R₂₀)_(m″)NR₁₃R₁₄;

[0428] R_(f) is heterocyclyl, heterocyclylC₁₋₁₀ alkyl or R₈;

[0429] v is 0, 1, or 2;

[0430] m is 0, 1, or 2;

[0431] m′ is 1 or 2;

[0432] m″ is 0, 1, 2, 3, 4, or 5;

[0433] R₂ hydrogen, C(H)(A)(R₂₂), —(CR₁₀R₂₃)_(n)OR₉, heterocylyl,heterocyclylC₁₋₁₀ alkyl, C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₁₀alkyl, C₅₋₇ cycloalkenyl, C₅₋₇cycloalkenylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, (CR₁₀R₂₃)_(n)OR₁₁,(CR₁₀R₂₃)_(n)S(O)_(m)R₁₈, (CR₁₀R₂₃)_(n)NHS(O)₂R₁₈, (CR₁₀R₂₃)_(n)NR₁₃R₁₄,(CR₁₀R₂₃)_(n)NO₂, (CR₁₀R₂₃)_(n)CN, (CR₁₀R₂₃)_(n)S(O)_(m′)NR₁₃R₁₄,(CR₁₀R₂₃)_(n)C(Z)R₁₁, (CR₁₀R₂₃)_(n)OC(Z)R₁₁, (CR₁₀R₂₃)_(n)C(Z)OR₁₁,(CR₁₀R₂₃)_(n)C(Z)NR₁₃R₁₄, (CR₁₀R₂₃)_(n)C(Z)NR₁₁OR₉,(CR₁₀R₂₃)_(n)NR₁₀C(Z)R₁, (CR₁₀R₂₃)_(n)NR₁₀C(Z)NR₁₃R₁₄,(CR₁₀R₂₃)_(n)N(OR₆)C(Z)NR₁₃R₁₄, (CR₁₀R₂₃)_(n)N(OR₆)C(Z)R₁₁,(CR₁₀R₂₃)_(n)C(═NOR₆)R₁₁, (CR₁₀R₂₃)_(n)NR₁₀C(═NR₁₉)NR₁₃R₁₄,(CR₁₀R₂₃)_(n)OC(Z)NR₁₃R₁₄, (CR₁₀R₂₃)_(n)NR₁₀C(Z)NR₁₃R₁₄,(CR₁₀R₂₃)_(n)NR₁₀C(Z)OR₁₀, 5-(R₁₈)-1,2,4-oxadiazol-3-yl or4-(R₁₂)-5-(R₁₈R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl,arylalkyl, heteroaryl, heteroaryl alkyl, cycloalkyl, cycloalkyl alkyl,heterocyclic and heterocyclic alkyl groups can be optionallysubstituted;

[0434] A is an optionally-substituted aryl, heterocyclyl or heteroarylring, or A is a substituted C₁₋₁₀ alkyl;

[0435] n is 0, or an integer having a value of 1 to 10;

[0436] Z is oxygen or sulfur;

[0437] R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR₇R₁₇,excluding the moieties —SR₅ being —SNR₇R₁₇ and —S(O)R₅ being —SOH;

[0438] R₆ is hydrogen, a pharmaceutically-acceptable cation, C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄alkyl, heterocyclyl, aroyl, or C₁₋₁₀ alkanoyl;

[0439] R₇ and R₁₇ are each independently selected from hydrogen or C₁₋₄alkyl, or R₇ and R₁₇ together with the nitrogen to which they areattached form a heterocyclic ring of 5 to 7 members which ringoptionally contains an additional heteroatom selected from oxygen,sulfur or NR₁₅;

[0440] R₈ is C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₁₁,(CR₁₀R₂₀)_(n)S(O)_(m)R₁₈, (CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, or(CR₁₀R₂₀)_(v)NR₁₃R₁₄, wherein the aryl, arylalkyl, heteroaryl, andheteroaryl alkyl can be optionally substituted;

[0441] R₉ is hydrogen, —C(Z)R₁₁, optionally-substituted C₁₋₁₀ alkyl,S(O)₂R₁₈, optionally-substituted aryl or optionally-substituted arylC₁₋₄alkyl;

[0442] R₁₀ and R₂₀ are each independently selected from hydrogen or C₁₋₄alkyl;

[0443] R₁₁ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl, wherein the aryl, arylalkyl, heteroaryl,heteroaryl alkyl, heterocyclyl or heterocyclylalkyl can be optionallysubstituted;

[0444] R₁₂ is hydrogen or R₁₆;

[0445] R₁₃ and R₁₄ are each independently selected from hydrogen oroptionally-substituted C₁₋₄ alkyl, optionally-substituted aryl oroptionally-substituted arylC₁₋₄ alkyl, or together with the nitrogen towhich they are attached form a heterocyclic ring of 5 to 7 members whichring optionally contains an additional heteroatom selected from oxygen,sulfur or NR₉;

[0446] R₁₅ is R₁₀ or C(Z)C₁₋₄ alkyl;

[0447] R₁₆ is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, or C₃₋₇cycloalkyl;

[0448] R₁₈ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl,arylC₁₋₁₀ alkyl, heterocyclyl, heterocyclylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl;

[0449] R₁₉ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or aryl; and

[0450] R₂₃ is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, orheterocyclylC₁₋₄ alkyl, all of which can be optionally substituted;

[0451] or a pharmaceutically-acceptable salt thereof.

[0452] Exemplary compounds of these formulas include:

[0453] 1-(pyrid-4-yl)-3-phenyl-5-(4-fluorophenyl)-1,2,4-triazole;

[0454]1-(6-aminopyrimidin-4-yl)-3-phenyl-5-(4-fluorophenyl)-1,2,4-triazole;

[0455]1-[4-(6,7-dimethoxyquinazoline)]-3-phenyl-5-(4-fluorophenyl)-1,2,4-triazole;

[0456]1-(4-fluorophenyl)-3-phenyl-5-(2-aminopyrimidin-4-yl)-1,2,4-triazole;

[0457]3-(4-fluorophenyl)-4-(2-aminopyrimidin-4-yl)-5-phenyl-1,2,4-triazole;

[0458] and pharmaceutically acceptable salts thereof.

[0459] Compounds useful in the practice of the present invention alsoinclude, but are not limited to, compounds of formula:

[0460] and the pharmaceutically acceptable salts thereof, or apharmaceutical composition thereof, wherein

[0461]

represents a single or double bond;

[0462] one Z² is CA or CR⁸A and the other is CR¹, CR¹ ₂, NR⁶ or Nwherein each R¹, R⁶ and R⁸ is independently hydrogen or noninterferingsubstituent;

[0463] A is —CO(X)_(j)Y wherein Y is COR² or an isostere thereof and R²is hydrogen or a noninterfering substituent, X is a spacer preferably2-6 Å in length, and j is 0 or 1;

[0464] Z³ is NR⁷ or O;

[0465] each R³ is independently a noninterfering substituent, wherein a“noninterfering substituent” is one that does not reduce the inhibitoractivity of the compound;

[0466] n is 0-3;

[0467] each of L¹ and L² is a linker;

[0468] each R⁴ is independently a noninterfering substituent;

[0469] m is 0-4;

[0470] Z¹ is CR⁵ or N wherein R⁵ is hydrogen or a noninterferingsubstituent;

[0471] each of l and k is an integer from 0-2 wherein the sum of l and kis 0-3;

[0472] Ar is an aryl group substituted with 0-5 noninterferingsubstituents, wherein two noninterfering substituents can form a fusedring; and

[0473] the distance between the atom of Ar linked to L² and the centerof the a ring is preferably 4.5-24 Å.

[0474] As used herein, a “noninterfering substituent” is a substituentwhich leaves the ability of the compound of formula (1) to inhibit p38-αactivity qualitatively intact. Thus, the substituent may alter thedegree of inhibition of p38-α. However, as long as the compound offormula (1) retains the ability to inhibit p38-α activity, thesubstituent will be classified as “noninterfering.” A number of assaysfor determining the ability of any compound to inhibit p38-α activityare available in the art. A whole blood assay for this evaluation isillustrated below: the gene for p38-α has been cloned and the proteincan be prepared recombinantly and its activity assessed, including anassessment of the ability of an arbitrarily chosen compound to interferewith this activity. The essential features of the molecule are tightlydefined. The positions which are occupied by “noninterferingsubstituents” can be substituted by conventional organic moieties as isunderstood in the art. It is irrelevant to the present invention to testthe outer limits of such substitutions. The essential features of thecompounds are those set forth with particularity herein.

[0475] Compounds useful in the practice of the present invention alsoinclude, but are not limited to, compounds of formulas:

[0476] pharmaceutically acceptable salts thereof, wherein

[0477] HET is a 5-7 membered heterocycle with 1 to 4 N, S or O atoms,which heterocycle is substituted with 1 to 3 C₁-C₄ branched or straightchain alkyl groups. HET can optionally be substituted with halo, cyano,N(R′)₂, OR′, CO₂R′, CON(R′)₂, and SO₂N(R²)₂;

[0478] X is O or NR′;

[0479] n is 1 to 3;

[0480] R′ is selected from hydrogen, (C₁-C₃)-alkyl, (C₂-C₃)-alkenyl oralkynyl, phenyl or phenyl substituted with 1 to 3 substituentsindependently selected from halo, methoxy, cyano, nitro, amino, hydroxy,methyl or ethyl; or a 5-6 membered heterocyclic ring system optionallysubstituted with 1 to 3 substituents independently selected from halo,methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl;

[0481] R₁ is selected from hydrogen, (C₁-C₃)-alkyl, hydroxy, or(C₁-C₃)-alkoxy;

[0482] R₂ is selected from hydrogen, (C₁-C₃)-alkyl, or(C₁-C₃)-alkenyloxy; each optionally substituted with —N(R′)₂, —OR′,—SR′, —C(O)—N(R′)₂, —S(O₂)—N(R′)₂, —C(O)—OR′, or R³; and

[0483] R³ is selected from 5-6 membered aromatic carbocyclic orheterocyclic ring systems.

[0484] Compounds useful in the practice of the present invention alsoinclude, but are not limited to, compounds of formulas:

[0485] wherein

[0486] R₁ is an aryl or heteroaryl ring, which ring is optionallysubstituted;

[0487] R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,heteroarylC₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkylmoiety; and wherein each of these moieties, excluding hydrogen, areoptionally substituted;

[0488] R₃ is a C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,arylC₁₋₁₀alkyl, heteroaryl C₁₋₁₀alkyl, or heterocyclylC₁₋₁₀ alkylmoiety; and wherein each of these moieties are optionally substituted;

[0489] X is R₂, OR₂, S(O)_(m)R₂ or (CH₂)_(n)NR₄R₁₄, or (CH₂)_(n)NR₂R₄;

[0490] n is 0 or an integer having a value of 1 to 10;

[0491] m is 0 or an integer having a value of 1 or 2;

[0492] R₄ and R₁₄ are each independently selected from hydrogen,optionally substituted C₁₋₁₄ alkyl, optionally substituted aryl, or anoptionally substituted arylC₁₋₄alkyl, or R₄ and R₁₄ together with thenitrogen to which they are attached form a heterocyclic ring of 5 to 7members, which ring optionally contains an additional heteroatomselected from oxygen, sulfur or NR₉, and which ring can be optionallysubstituted;

[0493] R₆ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclylC₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or aheteroarylC₁₋₁₀ alkyl moiety; and wherein each of these moieties,excluding hydrogen, can be optionally substituted;

[0494] R₉ is hydrogen, C(Z)R₆, optionally substituted C₁₋₁₀ alkyl,optionally substituted aryl or optionally substituted arylC₁₋₄ alkyl;

[0495] Z is oxygen or sulfur;

[0496] or a pharmaceutically acceptable salt thereof.

[0497] Compounds useful in the practice of the present invention alsoinclude, but are not limited to, compounds of formulas:

[0498] or pharmaceutically acceptable salts thereof, wherein

[0499] each of Q₁ and Q₂ are independently selected from 5-6 memberedaromatic carbo cyclic or hetero cyclic ring systems, or 8-10 memberedbicyclic ring systems comprising aromatic carbo cyclic rings, aromaticheterocyclic rings or a combination of an aromatic carbocyclic ring andan aromatic heterocyclic ring;

[0500] the rings that make up Q₁ are substituted with 1 to 4substituents, each of which is independently selected from halo; C₁-C₃alkyl optionally substituted with NR′₂, OR′, CO₂R′ or CONR₁₂;(C₁-C₃)-alkoxy optionally substituted with NR₁₂, OR′, CO₂R′ or CONR₁₂;NR₁₂; OCF₃; CF₃; NO₂; CO₂R′; CONR′; SR′; S(O₂)N(R′)₂; SCF₃; CN;N(R′)C(O)R⁴; N(R′)C(O)OR⁴; N(R′)C(O)C(O)R⁴; N(R′)S(O₂)R⁴; N(R′)R⁴;N(R⁴)₂; OR⁴; OC(O)R⁴; OP(O)₃H₂; or N═C—N(R′)₂;

[0501] the rings that make up Q₂ are optionally substituted with up to 4substituents, each of which is independently selected from halo; C₁-C₃straight or branched alkyl optionally substituted with NR₁₂, OR′, CO₂R′,S(O₂)N(R′)₂, N═C—N(R′)₂, R³, or CONR₁₂; (C₁-C₃)-alkoxy optionallysubstituted with NR₁₂, OR′, CO₂R′, S(O₂)N(R′)₂, N═C—N(R′)₂, R³, orCONR′₂; NR′₂, OCF₃; CF₃; NO₂; CO₂R′; CONR′; R³; OR³; NR³; SR³; C(O)R³;C(O)N(R′)R³; C(O)OR³; SR′; S(O₂)N(R′)₂; SCF₃; N═C—N(R′)₂; or CN;

[0502] R′ is selected from hydrogen, (C₁-C₃)-alkyl; (C₂-C₃)-alkenyl;(C₂-C₃) alkynyl; phenyl substituted with 1 to 3 substituentsindependently selected from halo, methoxy, cyano, nitro, amino, hydroxy,methyl or ethyl;

[0503] R³ is selected from 5-6 membered aromatic carbocyclic orheterocyclic ring systems;

[0504] R⁴ is (C₁-C₄)-alkyl optionally substituted with N(R′)₂, OR′,CO₂R′, CON(R′)₂, or SO₂N(R²)₂; or a 5-6 membered carbocyclic orheterocyclic ring system optionally substituted with N(R′)₂, OR′, CO₂R′,CON(R′)₂, or SO₂N(R²)₂;

[0505] X, if present, is selected from —S—, —O—, —S(O₂)—, —S(O)—,—S(O₂)—N(R²)—, —N(R²)—S(O₂)—, —N(R²)—C(O)O—, —O—C(O)—N(R²), —C(O)—,—C(O)O—, —O—C(O)—, —C(O)—N(R²)—, —N(R²)—C(O)—, —N(R²)—, —C(R²)₂—, or—C(OR²)₂—;

[0506] each R is independently selected from hydrogen, —R², —N(R²)₂,—OR², SR², —C(O)—N(R²)₂, —S(O₂)—N(R²)₂, or —C(O)—OR², wherein twoadjacent R are optionally bound to one another and, together with each Yto which they are respectively bound, form a 4-8 membered carbocyclic orheterocyclic ring;

[0507] R² is selected from hydrogen, (C₁-C₃)-alkyl, or (C₁-C₃)-alkenyl;each optionally substituted with —N(R′)₂, —OR′, SR′, —C(O)—N(R′)₂,—S(O₂)—N(R′)₂, —C(O)—OR′, or R³;

[0508] Y is N or C;

[0509] Z, if present, is N, NH, or, if chemically feasible, O;

[0510] A, if present, is N or CR′;

[0511] n is 0 or 1; and

[0512] R₁ is selected from hydrogen, (C₁-C₃)-alkyl, hydroxy, or(C₁-C₃)-alkoxy.

[0513] Compounds useful in the practice of the present invention alsoinclude, but are not limited to, compounds of formula:

[0514] wherein A is

[0515] (a)

[0516] wherein

[0517] R³′, R⁴, R are each independently H, C₁₋₁₀-alkyl, optionallysubstituted by halogen up to perhalo, C₁₋₁₀ alkoxy, optionallysubstituted by halogen, up to perhaloalkoxy, halogen; NO₂ or NH₂;

[0518] R^(6′) is H, C₁₋₁₀-alkyl, C₁₋₁₀ alkoxy, —NHCOR¹; —NR¹COR¹; NO₂;

[0519] one of R^(4′), R^(5′), or R^(6′) can be —X—Y; or

[0520] 2 adjacent R^(4′)—R^(6′) can together be an aryl or heteroarylring with 5-12 atoms, optionally substituted by C₁₋₁₀-alkyl, C₁₋₁₀alkoxy, C₃₋₁₀ cycloalkyl, C₂₋₁₀ alkenyl, C₁₋₁₀ alkanoyl, C₆₋₁₂ aryl,C₅₋₁₂ heteroaryl or C₆₋₁₂ arakyl;

[0521] R¹ is C₁₋₁₀-alkyl optionally substituted by halogen, up toperhalo;

[0522] X is —CH₂—, —S—, —N(CH₃)—, —NHC(O)—, —CH₂—S—, —S—CH₂—, —C(O)—, or—O—;

[0523] X is additionally a single bond where Y is pyridyl;

[0524] Y is phenyl, pyridyl, naphthyl, pyridone, pyrazine, benzodioxane,benzopyridine, pyrimidine or benzothiazole, each optionally substitutedby C₁₋₁₀-alkyl, C₁₋₁₀-alkoxy, halogen, OH, —SCH₃ or NO₂ or, where Y isphenyl, by

[0525] or a pharmaceutically-acceptable salt thereof;

[0526] or

[0527] (b)

[0528] wherein

[0529] R¹ is selected from the group consisting of C₃-C₁₀ alkyl, C₃-C₁₀cycloalkyl, up to per-halo substituted C₁-C₁₀ alkyl and up toper-halosubstituted C₃-C₁₀ cycloalkyl; and

[0530] R² is C₆-C₁₄ aryl, C₃-C₁₄ heteroaryl, substituted C₆-C₁₄ aryl orsubstituted C₃-C₁₄ heteroaryl;

[0531] wherein if R² is a substituted group, it is preferablysubstituted by one or more substituents independently selected from thegroup consisting of halogen, up to per-halosubstitution, and V_(n),where n=0-3 and each V is independently selected from the groupconsisting of —CN, —OC(O)NR⁵R^(5′),

[0532] —CO₂R⁵, —C(O)NR⁵R^(5′), —OR⁵, —SR⁵, —NR⁵R^(5′), —C(O)R⁵,—NR⁵C(O)OR^(5′), —SO₂R⁵—SOR⁵, —NR⁵C(O)R^(5′), —NO₂, C₁-C₁₀ alkyl, C₃-C₁₀cycloalkyl, C₆-C₁₄ aryl, C₃-C₁₃ heteroaryl, C₇-C₂₄ alkaryl, C₄-C₂₄alkheteroaryl, substituted C₁-C₁₀ alkyl, substituted C₃-C₁₀ cycloalkyl,substituted C₆-C₁₄ aryl, substituted C₃-C₁₃ heteroaryl, substitutedC₇-C₂₄ alkaryl and substituted C₄-C₂₄ alkheteroaryl;

[0533] wherein if V is a substituted group, it is substituted by one ormore substituents independently selected from the group consisting ofhalogen, up to per-halosubstitution, —CN, —CO₂R⁵, —C(O)R⁵,—C(O)NR⁵R^(5′), —NR⁵R^(5′), —OR⁵, —SR⁵, —NR⁵C(O)R^(5′), —NR⁵C(O)OR^(5′)and —NO₂; and

[0534] R⁵ and R^(5′) are independently selected form the groupconsisting of H, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₆-C₁₄ aryl, C₃-C₁₃heteroaryl, C₇-C₂₄ alkaryl, C₄-C₂₃ alkheteroaryl, up toper-halosubstituted C₁-C₁₀ alkyl, up to per-halosubstituted C₃-C₁₀cycloalkyl, up to per-halosubstituted C₆-C₁₄ aryl and up toper-halosubstituted C₃-C₁₃ heteroaryl;

[0535] or a pharmaceutically-acceptable salt thereof;

[0536] or

[0537] (c) a substituted moiety of up to 40 carbon atoms of the formula:-L-(M-L¹)_(q), where L is a 5- or 6-membered cyclic structure bounddirectly to D, L¹, comprises a substituted cyclic moiety having at least5 members, M is a bridging group having at least one atom, q is aninteger of from 1-3; and each cyclic structure of L and L¹ contains 0-4members of the group consisting of nitrogen, oxygen and sulfur;

[0538] L¹ is substituted by at least one substituent selected from thegroup consisting of —SO₂R_(x), —C(O)R_(x) and —C(NR_(y))R_(z);

[0539] R_(y) is hydrogen or a carbon-based moiety of up to 24 carbonatoms optionally containing heteroatoms selected from N, S and O andoptionally halosubstituted, up to perhalo;

[0540] R_(z) is hydrogen or a carbon-based moiety of up to 30 carbonatoms optionally containing heteroatoms selected from N, S and O andoptionally substituted by halogen, hydroxy and carbon-based substituentsof up to 24 carbon atoms, which optionally contain heteroatoms selectedfrom N, S and O and are optionally substituted by halogen; and

[0541] R_(x) is R_(z) or NR_(a)R_(b) where R_(a) and R_(b) are

[0542] i) independently hydrogen,

[0543] a carbon-based moiety of up to 30 carbon atoms optionallycontaining heteroatoms selected from N, S and O and optionallysubstituted by halogen, hydroxy and carbon-based substituents of up to24 carbon atoms, which optionally contain heteroatoms selected from N, Sand O and are optionally substituted by halogen, or

[0544] —OSi(R_(f))₃ where R_(f) is hydrogen or a carbon-based moiety ofup to 24 carbon atoms optionally containing heteroatoms selected from N,S and O and optionally substituted by halogen, hydroxy and carbon-basedsubstituents of up to 24 carbon atoms, which optionally containheteroatoms selected from N, S and O and are optionally substituted byhalogen; or

[0545] ii) R_(a) and R_(b) together form a 5-7 member heterocyclicstructure of 1-3 heteroatoms selected from N, S and O, or a substituted5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, Sand O, substituted by halogen, hydroxy or carbon-based substituents ofup to 24 carbon atoms, which optionally contain heteroatoms selectedfrom N, S and O and are optionally substituted by halogen; or

[0546] iii) one of R_(a) or R_(b) is —C(O)—, a C₁-C₅ divalent alkylenegroup or a substituted C₁-C₅ divalent alkylene group bound to the moietyL to form a cyclic structure with at least 5 members, wherein thesubstituents of the substituted C₁-C₅ divalent alkylene group areselected from the group consisting of halogen, hydroxy, and carbon-basedsubstituents of up to 24 carbon atoms, which optionally containheteroatoms selected from N, S and O and are optionally substituted byhalogen;

[0547] or a pharmaceutically-acceptable salt thereof; and

[0548] B is an unsubstituted or substituted, up to tricyclic, aryl orheteroaryl moiety with up to 30 carbon atoms with at least one 5- or6-membered aromatic structure containing 0-4 members of the groupconsisting of nitrogen, oxygen and sulfur;

[0549] wherein if B is substituted, it is substituted by one or moresubstituents selected from the group consisting of halogen, up toper-halo, and W_(n), wherein n is 0-3 and each W is independentlyselected from the group consisting of —CN, —CO₂R⁷, —C(O)NR⁷R⁷, —C(O)R⁷,—NO₂, —OR⁷, —SR⁷, —NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, C₁-C₁₀ alkyl,C₂₋₁₀-alkenyl, C₁₋₁₀-alkoxy, C₃-C₁₀ cycloalkyl, C₆-C₁₄ aryl, C₇-C₂₄alkaryl, C₃-C₁₃ heteroaryl, C₄-C₂₃ alkheteroaryl, substituted C₁-C₁₀alkyl, substituted C₂₋₁₀-alkenyl, substituted C₁₋₁₀-alkoxy, substitutedC₃-C₁₀ cycloalkyl, substituted C₄-C₂₃ alkheteroaryl and -Q-Ar;

[0550] wherein if W is a substituted group, it is substituted by one ormore substituents independently selected from the group consisting of—CN, —CO₂R⁷, —C(O)NR⁷R⁷, —C(O)R⁷, —NO₂, —OR⁷, —SR⁷, —NR⁷R⁷, —NR⁷C(O)OR⁷,—NR⁷C(O)R⁷ and halogen up to per-halo;

[0551] wherein each R⁷ is independently selected from H, C₁-C₁₀ alkyl,C₂₋₁₀-alkenyl, C₃-C₁₀ cycloalkyl, C₆-C₁₄ aryl, C₃-C₁₃ heteroaryl, C₇-C₂₄alkaryl, C₄-C₂₃ alkheteroaryl, up to per-halosubstituted C₁-C₁₀ alkyl,up to per-halosubstituted C₂₋₁₀-alkenyl, up to per-halosubstitutedC₃-C₁₀ cycloalkyl, up to per-halosubstituted C₆-C₁₄ aryl and up toper-halosubstituted C₃-C₁₃ heteroaryl;

[0552] wherein Q is —O—, —S—, —N(R)⁷, —(CH₂)-m, —C(O)—, —CH(OH)—,—NR⁷C(O)NR⁷R⁷—, —NR⁷C(O)—, —C(O)NR⁷—, —(CH₂)_(m)O—, —(CH₂)_(m)S—,—(CH₂)_(m)N(R⁷)—, —O(CH₂)_(m)—, CHX^(a), —CX^(a) ₂—, —S—(CH₂)_(m)— and—N(R⁷)(CH₂)_(m)—, where m=1-3, and X^(a) is halogen; and

[0553] Ar is a 5-10 member aromatic structure containing 0-4 members ofthe group consisting of nitrogen, oxygen and sulfur, which isunsubstituted or substituted by halogen up to per-halosubstitution andoptionally substituted by Z_(n1), wherein n1 is 0 to 3 and each Zsubstituent is independently selected from the group consisting of —CN,—CO₂R⁷, —C(O)NR⁷R⁷, —C(O)—NR⁷, —NO₂, —OR⁷, —SR⁷, —NR⁷R⁷, —NR⁷C(O)OR⁷,—C(O)R⁷, —NR⁷C(O)R⁷, C_-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₆-C₁₄ aryl,C₃-C₁₃ heteroaryl, C₇-C₂₄ alkaryl, C₄-C₂₃ alkheteroaryl, substitutedC₁-C₁₀ alkyl, substituted C₃-C₁₀ cycloalkyl, substituted C₇-C₂₄ alkaryland substituted C₄-C₂₃ alkheteroaryl; wherein the one or moresubstituents of Z are independently selected from the group consistingof —CN, —CO₂R⁷, —C(O)NR⁷R⁷, —OR⁷, —SR⁷, —NO₂, —NR⁷R⁷, —NR⁷C(O)R⁷ and—NR⁷C(O)OR⁷;

[0554] or a pharmaceutically-acceptable salt thereof.

[0555] Exemplary compounds of these formulas include:

[0556] N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-phenyloxyphenyl)urea;

[0557]N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(4-methoxyphenyloxy)phenyl)urea;N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(4-pyridinyloxy)phenyl)urea;

[0558]N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(4-pyridinylmethyl)phenyl)urea;

[0559]N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(4-pyridinylthio)phenyl)urea;

[0560]N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(4-(4,7-methano-H-isoindole-1,3(2H)-dionyl)methyl)phenyl)urea;

[0561] N-(5-tert-butyl-2-phenylphenyl)-N′-(2,3-dichlorophenyl)urea;

[0562] N-(5-tert-butyl-2-(3-thienyl)phenyl)-N′-(2,3-dichlorophenyl)urea;

[0563]N-(5-tert-butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N′-(2,3-dichlorophenyl)urea;

[0564]N-(5-tert-butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N′-(1-naphthyl)urea;

[0565]N-(5-tert-butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N′-(2,3-dichlorophenyl)urea;

[0566]N-(5-tert-butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N′-(1-naphthyl)urea;

[0567]N-(5-tert-butyl-2-(3-tetrahydrofuranyloxy)phenyl)-N′-(2,3-dichlorophenyl)urea;

[0568]N-(5-tert-butyl-2-methoxyphenyl)-N′-(4-(3-pyridinyl)methylphenyl)urea;

[0569] N-(5-trifluoromethyl-2-methoxyphenyl)-N′-(4-methylphenyl)urea;

[0570]N-(5-trifluoromethyl-2-methoxyphenyl)-N′-(4-methyl-2-fluorophenyl)urea;

[0571]N-(5-trifluoromethyl-2-methoxyphenyl)-N′-(4-fluoro-3-chlorophenyl)urea;

[0572]N-(5-trifluoromethyl-2-methoxyphenyl)-N′-(4-methyl-3-chlorophenyl)urea;

[0573]N-(5-trifluoromethyl-2-methoxyphenyl)-N′-(4-methyl-3-fluorophenyl)urea;

[0574]N-(5-trifluoromethyl-2-methoxyphenyl)-N′-(2,4-difluorophenyl)urea;

[0575]N-(5-trifluoromethyl-2-methoxyphenyl)-N′-(4-phenyloxy-3,5-dichlorophenyl)urea;

[0576]N-(5-trifluoromethyl-2-methoxyphenyl)-N′-(4-(4-pyridinylmethyl)phenyl)urea;

[0577]N-(5-trifluoromethyl-2-methoxyphenyl)-N′-(4-(4-pyridinylthio)phenyl)urea;

[0578]N-(5-trifluoromethyl-2-methoxyphenyl)-N′-(4-(4-pyridinyloxy)phenyl)urea;

[0579]N-(5-trifluoromethyl-2-methoxyphenyl)-N′-(3-(4-pyridinylthio)phenyl)urea;

[0580]N-(5-trifluoromethyl-2-methoxyphenyl)-N′-(4-(3-(N-methylaminocarbonyl)phenyloxy)phenyl)urea;

[0581] N-(5-fluorosulfonyl)-2-methoxyphenyl)-N′-(4-methylphenyl)urea;

[0582]N-(5-(difluromethanesulfonyl)-2-methoxyphenyl)-N′-(4-methylphenyl)urea;

[0583]N-(5-(difluoromethanesulfonyl)-2-methoxyphenyl)-N′-(4-fluorophenyl)urea;

[0584]N-(5-(difluoromethanesulfonyl)-2-methoxyphenyl)-N′-(4-methyl-2-fluorophenyl)urea;

[0585]N-(5-(difluoromethanesulfonyl)-2-methoxyphenyl)-N′-(4-methyl-3-fluorophenyl)urea;

[0586]N-(5-(difluoromethanesulfonyl)-2-methoxyphenyl)-N′-(4-methyl-3-chlorophenyl)urea;

[0587]N-(5-(difluoromethanesulfonyl)-2-methoxyphenyl)-N′-(4-fluoro-3-chlorophenyl)urea;

[0588]N-(5-(difluoromethanesulfonyl)-2-methoxyphenyl)-N′-(4-fluoro-3-methylphenyl)urea;

[0589]N-(5-(difluoromethanesulfonyl)-2-methoxyphenyl)-N′-(2,3-dimethylphenyl)urea;

[0590]N-(5-(trifluoromethanesulfonyl)-2-methoxphenyl)-N′-(4-methylphenyl)urea;

[0591] N-(3-methoxy-2-naphthyl)-N′-(2-fluorophenyl)urea;

[0592] N-(3-methoxy-2-naphthyl)-N′-(4-methylphenyl)urea;

[0593] N-(3-methoxy-2-naphthyl)-N′-(3-fluorophenyl)urea;

[0594] N-(3-methoxy-2-naphthyl)-N′-(4-methyl-3-fluorophenyl)urea;

[0595] N-(3-methoxy-2-naphthyl)-N′-(2,3-dimethylphenyl)urea;

[0596] N-(3-methoxy-2-naphthyl)-N′-(1-naphthyl)urea;

[0597] N-(3-methoxy-2-naphthyl)-N′-(4-(4-pyridinylmethyl)phenyl)urea;

[0598] N-(3-methoxy-2-naphthyl)-N′-(4-(4-pyridinylthio)phenyl)urea;

[0599] N-(3-methoxy-2-naphthyl)-N′-(4-(4-methoxyphenyloxy)phenyl)urea;

[0600]N-(3-methoxy-2-naphthyl)-N′-(4-(4-(4,7-methano-1H-isoindole-1,3(2H)-dionyl)methyl)phenyl)urea;

[0601] N-(2-hydroxy-4-nitro-5-chlorophenyl)-N′-(phenyl)urea;

[0602]N-(2-hydroxy-4-nitro-5-chlorophenyl)-N′-(4-(4-pyridinylmethyl)phenyl)urea;

[0603] and pharmaceutically acceptable salts thereof.

[0604] Such compounds are described in published PCT applications WO96/21452, WO 96/40143, WO 97/25046, WO 97/35856, WO 98/25619, WO98/56377, WO 98/57966, WO 99/32110, WO 99/32121, WO 99/32463, WO99/61440, WO 99/64400, WO 00/10563, WO 00/17204, WO 00/19824, WO00/41698, WO 00/64422, WO 00/71535, WO 01/38324, WO 01/64679, WO01/66539, and WO 01/66540, each of which is herein incorporated byreference.

[0605] In all instances herein where there is an alkenyl or alkynylmoiety as a substituent group, the unsaturated linkage, i.e., thevinylene or acetylene linkage, is preferably not directly attached tothe nitrogen, oxygen or sulfur moieties, for instance in OR_(f), or forcertain R₂ moieties.

[0606] As used herein, “optionally substituted” unless specificallydefined shall mean such groups as halogen, such as fluorine, chlorine,bromine or iodine; hydroxy; hydroxy-substituted C₁₋₁₀alkyl; C₁₋₁₀alkoxy, such as methoxy or ethoxy; S(O)_(m) alkyl, wherein m is 0, 1 or2, such as methyl thio, methylsulfinyl or methyl sulfonyl; amino, monoand di-substituted amino, such as in the NR₇R₁₇ group; or where theR₇R₁₇ can together with the nitrogen to which they are attached cyclizeto form a 5- to 7-membered ring which optionally includes an additionalheteroatom selected from O, N, and S; C₁₋₁₀ alkyl, cycloalkyl, orcycloalkyl alkyl group, such as methyl, ethyl, propyl, isopropyl,t-butyl, etc. or cyclopropyl methyl; halo-substituted C₁₋₁₀ alkyl, suchas CF₃; an optionally substituted aryl, such as phenyl, or an optionallysubstituted arylalkyl, such as benzyl or phenethyl, wherein these arylmoieties can also be substituted one to two times by halogen; hydroxy;hydroxy-substituted alkyl; C₁₋₁₀ alkoxy; S(O)_(m) alkyl; amino, mono-and di-substituted amino, such as in the NR₇R₁₇ group; alkyl, or CF₃.

[0607] Inhibitors useful in the present invention can be used with anypharmaceutically acceptable salt. The term “pharmaceutically acceptablesalts” refers to salts prepared from pharmaceutically acceptablenon-toxic bases or acids. When the compound utilized by the presentinvention is acidic, its corresponding salt can be conveniently preparedfrom pharmaceutically acceptable non-toxic bases, including inorganicbases and organic bases. Salts derived from such inorganic bases includealuminum, ammonium, calcium, copper (ic and ous), ferric, ferrous,lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc andthe like salts. Particularly preferred are the ammonium, calcium,magnesium, potassium and sodium salts. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, as well as cyclic amines andsubstituted amines such as naturally occurring and synthesizedsubstituted amines. Basic salts of inorganic and organic acids alsoinclude as hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methane sulphonic acid, ethane sulphonic acid, aceticacid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid,phenylacetic acid and mandelic acid. In addition,pharmaceutically-acceptable salts of the above-described compounds canalso be formed with a pharmaceutically-acceptable cation, for instance,if a substituent group comprises a carboxy moiety. Suitablepharmaceutically-acceptable cations are well known to those skilled inthe art and include alkaline, alkaline earth, ammonium and quaternaryammonium cations.

[0608] Other pharmaceutically acceptable organic non-toxic bases fromwhich salts can be formed include ion exchange resins such as, forexample, arginine, betaine, caffeine, choline,N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, tromethamineand the like.

[0609] The inhibitors of p38 MAP kinase can be used as singletherapeutic agents or in combination with other therapeutic agents.Drugs that could be usefully combined with these compounds includemonoclonal antibodies targeting cells of the immune system, antibodiesor soluble receptors or receptor fusion proteins targeting immune ornon-immune cytokines, and small molecule inhibitors of cell division,protein synthesis, or mRNA transcription or translation, or inhibitorsof immune cell differentiation, activation, or function (e.g., cytokinesecretion).

[0610] The following terms, as used herein, refer to:

[0611] “halo” or “halogens”, include the halogens: chloro, fluoro, bromoand iodo;

[0612] “C₁₋₁₀alkyl” or “alkyl”—both straight and branched chain radicalsof 1 to 10 carbon atoms, unless the chain length is otherwise limited,including, but not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like;

[0613] the term “cycloalkyl” is used herein to mean cyclic radicals,preferably of 3 to 8 carbons, including but not limited to cyclopropyl,cyclopentyl, cyclohexyl, and the like;

[0614] the term “cycloalkenyl” is used herein to mean cyclic radicals,preferably of 5 to 8 carbons, which have at least one double bond,including but not limited to cyclopentenyl, cyclohexenyl, and the like;

[0615] the term “alkenyl” is used herein at all occurrences to meanstraight or branched chain radical of 2-10 carbon atoms, unless thechain length is limited thereto, wherein there is at least one doublebond between two carbon atoms in the chain, including, but not limitedto ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl and the like;

[0616] “aryl”—phenyl and naphthyl;

[0617] “heteroaryl” (on its own or in any combination, such as“heteroaryloxy” or “heteroaryl alkyl”)—a 5-10-membered aromatic ringsystem in which one or more rings contain one or more heteroatomsselected from the group consisting of N, O and S, such as, but notlimited, to pyrrole, pyrazole, furan, thiophene, quinoline,isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole,thiadiazole, triazole, imidazole, or benzimidazole;

[0618] “heterocyclic” (on its own or in any combination, such as“heterocyclylalkyl”)—a saturated or partially unsaturated 4-10-memberedring system in which one or more rings contain one or more heteroatomsselected from the group consisting of N, O, and S; such as, but notlimited to, pyrrolidine, piperidine, piperazine, morpholine,tetrahydropyran, or imidazolidine;

[0619] the term “aralkyl” or “heteroarylalkyl” or “heterocyclicalkyl” isused herein to mean C!4 alkyl as defined above attached to an aryl,heteroaryl or heterocyclic moiety as also defined herein unlessotherwise indicate;

[0620] “sulfinyl”—the oxide S(O) of the corresponding sulfide, the term“thio” refers to the sulfide, and the term “sulfonyl” refers to thefully oxidized S(O)₂ moiety;

[0621] “aroyl”—a C(O)Ar, wherein Ar is as phenyl, naphthyl, or arylalkyl derivative such as defined above, such groups include but are notlimited to benzyl and phenethyl; and

[0622] “alkanoyl”—a C(O)C₁₋₁₀ alkyl wherein the alkyl is as definedabove.

[0623] For the purposes herein the “core” 4-pyrimidinyl moiety for R₁ orR₂ is referred to as the formula:

[0624] The compounds useful in the practice of the present invention cancontain one or more asymmetric carbon atoms and can exist in racemic andoptically active forms. The use of all of these compounds are includedwithin the scope of the present invention.

[0625] Compounds useful in the practice of the present invention alsoinclude, but are not limited to, the compounds shown in Tables A-C,below. TABLE A Citations, each of which is herein Chemical Structureincorporated by reference.

WO-00166539, WO-00166540, WO-00164679, WO-00138324, WO-00064422,WO-00019824, WO-00010563, WO-09961440, WO-09932121, WO-09857966,WO-09856377, WO-09825619, WO-05756499, WO-09735856, WO-09725046,WO-09640143, WO-09621452; Gallagher, T. F., et. Al., # Bioorg. Med.Chem. 5:49 (1997); Adams, J. L., et al., Bioorg. Med. Chem. Lett.8:3111-3116 (1998)

De Laszlo, S. E., et. Al., Bioorg Med Chem Lett. 8:2698 (1998)

WO-09957101; Poster presentation at the 5^(th) World Congress onInflammation, Edinburgh, UK. (2001)

WO-00041698, WO-09932110, WO-09932463

WO-00017204, WO-09964400

Revesz. L., et. al., Bioorg Med Chem Lett. 10:1261 (2000)

WO-00207772

Fijen, J. W., et al., Clin. Exp. Immunol. 124:16-20 (2001); Wadsworth,S. A., et. al., J. Pharmacol. Expt. Therapeut. 291:680 (1999)

Collis, A. J., et al.. Bioorg. Med. Chem. Lett. 11:693-696 (2001);McLay, L. M., et al., Bioorg Med Chem 9:537-554 (2001)

WO-00110865, WO-00105749

[0626] TABLE B Compd. # STRUCTURE 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

Compd. # MOLSTRUCTURE 117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

[0627] The compounds described above are provided for guidance andexample only. It should be understood that other modulators of p38kinase are useful in the invention provided that they exhibit adequateactivity relative to the target protein.

[0628] Formulations and Methods of Administration

[0629] A pharmaceutical composition useful in the present inventioncomprises a p38 MAP kinase inhibitor (such as those described above) anda pharmaceutically acceptable carrier, excipient, diluent and/or salt.

[0630] Pharmaceutically acceptable carrier, diluent, excipient, and/orsalt means that the carrier, diluent, excipient and/or salt must becompatible with the other ingredients of the formulation, does notadversely affect the therapeutic benefit of the p38 MAP kinaseinhibitor, and is not deleterious to the recipient thereof.

[0631] Administration of the compounds or pharmaceutical compositionsthereof for practicing the present invention can be by any method thatdelivers the compounds systemically and/or locally (e.g., at the site ofthe bone fracture, osteotomy, or orthopedic surgery). These methodsinclude oral routes, parenteral routes, intraduodenal routes, etc.

[0632] In local applications, the compound or pharmaceutical compositionis applied to the sites of bone fractures, osteotomies or grafts, forexample, either by injection of the compound in a suitable solvent(e.g., an oily solvent such as arachis oil) to the fracture site or bonehealing site or, in cases of open surgery, by local application theretoof such compounds in a suitable carrier such as bone-wax, demineralizedbone powder, polymeric bone cements, bone sealants, polylactic acid,polyglycolic acid, polylactic acid-polyglycolic acid, etc.Alternatively, local application can be achieved by applying a solutionor dispersion of the compound in a suitable carrier onto the surface orincorporating it into solid or semi-solid implants conventionally usedin orthopedic surgery, such as dacron-mesh, gel-foam and kiel bone, orprostheses.

[0633] For topical applications, the compound or pharmaceuticalcomposition thereof can be formulated in a suitable ointment containingthe active component suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax, sugars such as lactose and water.Alternatively, the pharmaceutical compositions can be formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

[0634] Depending on the particular condition, disorder or disease to betreated, additional therapeutic agents can be administered together withthe p38 MAP kinase inhibitors. Those additional agents can beadministered sequentially in any order, as part of a multiple dosageregimen, from the p38 MAP kinase inhibitor-containing composition(consecutive or intermittent administration). Alternatively, thoseagents can be part of a single dosage form, mixed together with the p38MAP kinase inhibitor in a single composition (simultaneous or concurrentadministration).

[0635] For oral administration, a pharmaceutical composition useful inthe invention can take the form of solutions, suspensions, tablets,pills, capsules, powders, granules, semisolids, sustained releaseformulations, elixirs, aerosols, and the like. Tablets containingvarious excipients such as sodium citrate, calcium carbonate and calciumphosphate are employed along with various disintegrants such as starch,preferably potato or tapioca starch, and certain complex silicates,together with binding agents such as polyvinylpyrrolidone, sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often very useful fortabletting purposes. Solid compositions of a similar type are alsoemployed as fillers in soft and hard-filled gelatin capsules; preferredmaterials in this connection also include lactose or milk sugar as wellas high molecular weight polyethylene glycols. When aqueous suspensionsand/or elixirs are desired for oral administration, the compounds ofthis invention can be combined with various sweetening agents, flavoringagents, coloring agents, emulsifying agents and/or suspending agents, aswell as such diluents as water, ethanol, propylene glycol, glycerin andvarious like combinations thereof.

[0636] The choice of formulation depends on various factors such as themode of drug administration (e.g., for oral administration, formulationsin the form of tablets, pills or capsules are preferred) and thebioavailability of the drug substance. Recently, pharmaceuticalformulations have been developed especially for drugs that show poorbioavailability based upon the principle that bioavailability can beincreased by increasing the surface area i.e., decreasing particle size.For example, U.S. Pat. No. 4,107,288 describes a pharmaceuticalformulation having particles in the size range from 10 to 1,000 nm inwhich the active material is supported on a crosslinked matrix ofmacromolecules. U.S. Pat. No. 5,145,684 describes the production of apharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 nm) in the presence of asurface modifier and then dispersed in a liquid medium to give apharmaceutical formulation that exhibits remarkably highbioavailability.

[0637] The term “parenteral” as used herein refers to modes ofadministration which include intravenous, intramuscular,intraperitoneal, intrasternal, subcutaneous, intramedullary andintraarticular injection and infusion. A pharmaceutical composition forparenteral injection can comprise pharmaceutically acceptable sterileaqueous or nonaqueous solutions, dispersions, suspensions or emulsionsas well as sterile powders for reconstitution into sterile injectablesolutions or dispersions just prior to use. Aqueous solutions areespecially suitable for intravenous, intramuscular, subcutaneous andintraperitoneal injection purposes. In this connection, the sterileaqueous media employed are all readily obtainable by standard techniqueswell-known to those skilled in the art. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), carboxymethylcellulose and suitable mixturesthereof, vegetable oils (such as olive oil), and injectable organicesters such as ethyl oleate. Proper fluidity can be maintained, forexample, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions,and by the use of surfactants.

[0638] The pharmaceutical compositions useful in the present inventioncan also contain adjuvants such as, but not limited to, preservatives,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, such as for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of the injectable pharmaceutical formcan be brought about by the inclusion of agents that delay absorptionsuch as aluminum monostearate and gelatin.

[0639] In some cases, in order to prolong the effect of the drugs, it isdesirable to slow the absorption from subcutaneous or intramuscularinjection. This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, can depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

[0640] Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such as polylactide,polyglycolide, and polylactide-polyglycolide. Depending upon the ratioof drug to polymer and the nature of the particular polymer employed,the rate of drug release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping the drugin liposomes or microemulsions that are compatible with body tissues.

[0641] The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

[0642] Administration by slow infusion is particularly useful whenintrathecal or epidural routes are employed. A number of implantable orbody-mountable pumps useful in delivering compound at a regulated rateare known in the art. See, e.g., U.S. Pat. No. 4,619,652.

[0643] Suspensions, in addition to the active compounds, can containsuspending agents as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth,and mixtures thereof.

[0644] For purposes of transdermal (e.g., topical) administration,dilute sterile, aqueous or partially aqueous solutions (usually in about0.1% to 5% concentration), otherwise similar to the above parenteralsolutions, are prepared.

[0645] The pharmaceutical compositions useful in the invention can alsobe administered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and can be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

[0646] In nonpressurized powder compositions, the active ingredients infinely divided form can be used in admixture with a larger-sizedpharmaceutically acceptable inert carrier comprising particles having asize, for example, of up to 100 μm in diameter. Suitable inert carriersinclude sugars such as lactose. Desirably, at least 95% by weight of theparticles of the active ingredient have an effective particle size inthe range of 0.01 to 10 μm.

[0647] Alternatively, the composition can be pressurized and contain acompressed gas, such as, e.g., nitrogen, carbon dioxide or a liquefiedgas propellant. The liquefied propellant medium and indeed the totalcomposition are preferably such that the active ingredients do notdissolve therein to any substantial extent. The pressurized compositioncan also contain a surface active agent. The surface active agent can bea liquid or solid non-ionic surface active agent or can be a solidanionic surface active agent. It is preferred to use the solid anionicsurface active agent in the form of a sodium salt.

[0648] Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of theinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the drugs.

[0649] The compositions useful in the present invention can also beadministered in the form of liposomes. As is known in the art, liposomesare generally derived from phospholipids or other lipid substances.Liposomes are formed by mono- or multi-lamellar hydrated liquid crystalsthat are dispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes can beused. The present compositions in liposome form can contain, in additionto the compounds of the invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andthe phosphatidyl cholines (lecithins), both natural and synthetic.Methods to form liposomes are known in the art (see e.g., Prescott, E.,Meth. Cell Biol. 14:33 (1976)).

[0650] Other pharmaceutically acceptable carrier includes, but is notlimited to, a non-toxic solid, semisolid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type, includingbut not limited to ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

[0651] Solid pharmaceutical excipients include, but are not limited to,starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice,flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerolmonostearate, sodium chloride, dried skim milk and the like. Liquid andsemisolid excipients can be selected from glycerol, propylene glycol,water, ethanol and various oils, including those of petroleum, animal,vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineraloil, sesame oil, etc. Preferred liquid carriers, particularly forinjectable solutions, include water, saline, aqueous dextrose, andglycols.

[0652] Methods of preparing various pharmaceutical compositions with acertain amount of active ingredient are known, or will be apparent inlight of this disclosure, to those skilled in this art. Other suitablepharmaceutical excipients and their formulations are described inRemington's Pharmaceutical Sciences, edited by E. W. Martin, MackPublishing Company, 19th ed. (1995).

[0653] Pharmaceutical compositions useful in the present invention cancontain 0.1%-95% of the compound(s) of this invention, preferably1%-70%. In any event, the composition or formulation to be administeredwill contain a quantity of a compound(s) according to this invention inan amount effective to treat the condition, disorder or disease of thesubject being treated.

[0654] One of ordinary skill in the art will appreciate thatpharmaceutically effective amounts of the p38 MAP kinase inhibitor canbe determined empirically and can be employed in pure form or, wheresuch forms exist, in pharmaceutically acceptable salt, ester or prodrugform. The agents can be administered to a patient as pharmaceuticalcompositions in combination with one or more pharmaceutically acceptableexcipients. It will be understood that, when administered to, forexample, a human patient, the total daily usage of the agents orcomposition of the present invention will be decided within the scope ofsound medical judgement by the attending physician. The specifictherapeutically effective dose level for any particular patient willdepend upon a variety of factors: the type and degree of the cellularresponse to be achieved; activity of the specific agent or compositionemployed; the specific agents or composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of theagent; the duration of the treatment; drugs used in combination orcoincidental with the specific agent; and like factors well known in themedical arts. For example, it is well within the skill of the art tostart doses of the agents at levels lower than those required to achievethe desired therapeutic effect and to gradually increase the dosagesuntil the desired effect is achieved.

[0655] For example, satisfactory results are obtained by oraladministration of the compounds at dosages on the order of from 0.05 to500 mg/kg/day, preferably 0.1 to 100 mg/kg/day, more preferably 1 to 50mg/kg/day, administered once or, in divided doses, 2 to 4 times per day.On administration parenterally, for example, by i.v. bolus, drip orinfusion, dosages on the order of from 0.01 to 1000 mg/kg/day,preferably 0.05 to 500 mg/kg/day, and more preferably 0.1 to 100mg/kg/day, can be used. Suitable daily dosages for patients are thus onthe order of from 2.5 to 500 mg p.o., preferably 5 to 250 mg p.o., morepreferably 5 to 100 mg p.o., or on the order of from 0.5 to 250 mg i.v.,preferably 2.5 to 125 mg i.v. and more preferably 2.5 to 50 mg i.v.

[0656] Dosaging can also be arranged in a patient specific manner toprovide a predetermined concentration of the agents in the blood, asdetermined by techniques accepted and routine in the art (HPLC ispreferred). Thus patient dosaging can be adjusted to achieve regularon-going blood levels, as measured by HPLC, on the order of from 50 to5000 ng/ml, preferably 100 to 2500 ng/ml.

[0657] Kits

[0658] The invention also relates to combining separate pharmaceuticalcompositions in kit form useful for bone healing. The kit can have acarrier means being compartmentalized in close confinement to receivetwo or more container means therein, having (1) a first container meanscontaining a therapeutically effective amount of a p38 MAP kinaseinhibitor and (2) a second container means containing a therapeuticallyeffective amount of carrier, excipient or diluent. Optionally, the kitcan have additional container mean(s) containing a therapeuticallyeffective amount of additional agents.

[0659] The kit comprises a container for containing the separatecompositions such as a divided bottle or a divided foil packet, however,the separate compositions can also be contained within a single,undivided container. Typically the kit comprises directions foradministration of the separate components. The kit form is particularlyadvantageous when the separate components are preferably administered indifferent dosage forms (e.g., oral and parenteral) or at differentdosage intervals, or when titration of the individual components of thecombination is desired by the prescribing physician.

[0660] An example of such a kit is a so-called blister pack. Blisterpacks are well known in the packaging industry and are being widely usedfor the packaging of pharmaceutical unit dosage forms (tablets,capsules, and the like). Blister packs generally consist of a sheet ofrelatively stiff material covered with a foil of a preferablytransparent plastic material. During the packaging process, recesses areformed in the plastic foil. The recesses have the size and shape of thetablets or capsules to be packed. Next, the tablets or capsules areplaced in the recesses and the sheet of relatively stiff material issealed against the plastic foil at the face of the foil which isopposite from the direction in which the recesses were formed. As aresult, the tablets or capsules are sealed in the recesses between theplastic foil and the sheet. Preferably the strength of the sheet is suchthat the tablets or capsules can be removed from the blister pack bymanually applying pressure on the recesses whereby an opening is formedin the sheet at the place of the recess. The tablet or capsule can thenbe removed via said opening.

[0661] It can be desirable to provide a memory aid on the kit, e.g., inthe form of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the dosage form sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card e.g., “First Week, Monday, Tuesday . . .Second Week, Monday, Tuesday . . . ” etc. Other variations of memoryaids will be readily apparent. A “daily dose” can be a single tablet orcapsule or several tablets or capsules to be taken on a given day. Also,a daily dose of the compound, a prodrug thereof, or a pharmaceuticallyacceptable salt of the compound can consist of one tablet or capsulewhile a daily dose of the second compound can consist of several tabletsor capsules and vice versa. The memory aid should reflect this.

[0662] It will be readily apparent to one of ordinary skill in therelevant arts that other suitable modifications and adaptations to themethods and applications described herein can be made without departingfrom the scope of the invention or any embodiment thereof.

[0663] The following examples are offered to illustrate but not to limitthe invention.

EXAMPLES Example 1

[0664] It has been found that fracture healing in rats treated with aCOX-2 inhibitor, rofecoxib (Vioxx, Merck Co.) or celecoxib (Celebrex,Pharmacia Corp.), was dramatically impaired.

[0665] Histological studies indicated that COX-2 function is essentialfor endochondral ossification during the fracture healing process. COX-2is induced by pro-inflammatory stimuli and the prostaglandins made byCOX-2 can enhance inflammation. Inflammation is an early phase offracture healing and it has been theorized that inflammation initiatesthe bone healing cascade of molecular and cellular events. Therefore, itwas also hypothesized that the inflammation event itself was importantfor initiating and maintaining the fracture healing cascade and notstrictly a function of COX-2.

[0666] Closed femur fractures were made in female retired breederSprague-Dawley rats. The rats were given oral doses of the p38 MAPkinase inhibitor (compound 25, Table B)(30 mg/kg) once or twice per dayand either vehicle only (control) or rofecoxib (Vioxx, 3 mg/kg, once aday) as a positive control for fracture inhibition. The data indicatedthat the p38 MAP kinase inhibitor does not negatively affect fracturehealing and can actually enhance or accelerate the healing process.

[0667] The histological analysis indicated that the p38 MAP kinaseinhibitor enhanced fracture healing by increasing and/or acceleratingcalcified cartilage formation as well as new bone formation. Potentialchanges in the distal femur growth plate of the p38 MAP kinase inhibitortreated rats suggested that the p38 MAP kinase inhibitor could beaffecting growth plate chondrocyte metabolism.

[0668] Osteoclasts were noted within the fracture calluses of the p38MAP kinase inhibitor treated rats. The amount of osteoclasts was notquantified but appeared to approximate levels found in control rats.

[0669] Results

[0670] Drug Dosing and Fracture Production

[0671] The initial set of 24 rats used for these experiments wasdesignated group A (Table 4). These rats received drug in PEG300 asvehicle and at a dose of 1 ml/kg. Six of the 24 rats in group A diedfrom apparent toxicity to either the batch of PEG300 or the 1 ml/kg dosesince rats died in each of the 4 treatment categories. A seventh rat waseuthanized due to its poor appearance, also apparently from the PEG300toxicity effect. Among the remaining rats, a general poor state ofhealth was observed with rats not eating or drinking and demonstrating avery lethargic behavior during the five days of drug administration. Toalleviate this problem, a different batch of PEG300 (Sigma) was used andthe dose was dropped to 0.5 ml/kg for the remainder of the animals used(rats 25-124). No further PEG300 toxicity was observed.

[0672] The prior set of experiments examining the effects ofCOX-2-selective NSAIDs on fracture healing used retired breeder maleSprague-Dawley rats with an average size of approximately 600 g. Tostabilize the femur fractures in these animals, a stainless steel rodwith a diameter of 1.1 mm was used. This same diameter rod wascontinually used during the initial phases of this study even though250-300 g retired breeder female Sprague-Dawley rats were used. Thequality of the femur fractures produced was poor in these rats (Groups Aand B, Table 4). It was hypothesized that the 1.1 mm diameter rod wastoo stiff and was actually creating comminuted fractures. To test thishypothesis 0.8 and 0.9 mm diameter rods were used for fracturestabilization in the smaller female rats (rats 58 and 59, Table 4). The0.8 mm diameter rod appeared to work slightly better than the 0.9 mmdiameter rod and so the 0.8 mm diameter rod was used for the remainderof these experiments (Group C, Table 4). After switching to the smallerdiameter rod, fracture quality increased to levels comparable to thatpreviously obtained using the larger male rats; only 7 of the 65 rats ingroup C were immediately disqualified from the study due to poorfracture quality (see Appendix A).

[0673] Radiographic Analysis

[0674] All rats were radiographed at time of sacrifice andrepresentative radiographs can be found in FIGS. 1A-1I, 2A-2F, 3A-3E,and 4A-4H. Using the scoring system described in the Materials andMethods section, infra, the 4 week post-fracture radiographs from thep38 MAP kinase inhibitor treated rats had significantly higher scoresthan the control or rofecoxib treated rats (see Table 1). Theseobservations are clearly indicative of advanced healing in the p38 MAPkinase inhibitor treated rats.

[0675] Radiographs from the control rats at 4 weeks post-fractureappeared to be following a normal healing response (FIGS. 1A-1I). In themajority of the control rats, the fracture was not bridged at eitherapex of the fracture callus or by new bone formation at the corticalbone ends of fracture site. An example of rat that shows no bridging wasrat #65 (FIG. 1A). In contrast, bridging at the apex of the fracturecallus and new bone formation (characterized by a cotton-ball-likeappearance) was evident at the fracture site in the top-half of thefracture callus from rat #114 (FIG. 1H). The negative effects ofrofecoxib on fracture healing were evident in the radiographs shown inFIGS. 2A-2F. In most of the fractures, the fracture site was stillplainly evident and little or no bridging was evident. An exception wasrat #96 (FIG. 2B) where bridging is evident. Note that the radiographfor rat #123 (FIG. 2F) appeared to have been made with the femur at anangle (not perpendicular between the X-ray beam and the femur's longaxis) and thus though it can appear to be bridged, the circular patternwithin the radiograph indicates that it was not bridged.

[0676] p38 MAP kinase inhibitor treatment appears to acceleratedfracture healing as per the radiographic analysis (see FIGS. 3A-3E and4A-4H and Table 1). As can be seen in FIG. 3A for rat #60, the top apexof the fracture callus was clearly bridged and new bone formation(cotton-ball-like appearance) also appeared to be bridging the top ofthe fracture in this animal. In contrast, the apex of the bottom half ofthis callus (Rat #60) did not appear to be bridged. Similar and evenbetter examples of accelerated healing were found among the otherradiographs of the p38 MAP kinase inhibitor treated rats. Note that theradiograph for rat #61 (FIG. 6B) is indicative of reactive boneformation caused by infection, but no evidence of infection (other thanthe X-ray) was found when this femur was harvested for mechanicaltesting. TABLE 1 Radiographic comparisons between treatment groups at 4weeks post-fracture in Group C rats (rats 60-124). p38 MAP Kinase p38MAP Kinase Control Rofecoxib Inhibitor Inhibitor × 2 Mean 1.33 0.83 3.23.75 Range 0-4 0-3 3-4 3-4 Sample size 9 6 5 8 P value* — 0.46 <0.01<0.001

[0677] Mechanical Analysis

[0678] Torsional mechanical testing was performed on the fractured(right) and contralateral (left) femurs from control, rofecoxib (3mg/kg/day); p38 MAP kinase inhibitor (30 mg/kg/day), and p38 MAP kinaseinhibitor (2×30 mg/kg/day). The stabilizing rods were removed from thefemurs prior to testing and the femurs were wrapped in saline soakedgauze to prevent dehydration prior to testing. The ends of the femurswere potted in hex nuts with Wood's metal and the peak torque and anglefailure determined using an MTS servohydraulic mechanical testingmachine and a 20 Nm reaction torque load cell as per standard procedures(Simon, A. M. et al., J. Bone Miner. Res. 17:963-976 (2002)). Femur andfracture callus dimensions and gage length were measured before andafter mechanical testing using digital calipers. The values obtainedwere used to calculate torsional rigidity, and shear stress as described(Simon, A. M. et al., J. Bone Min. Res., in press (2002)). Finally, thedata was normalized as the percentage of the fractured femur relative tothe contralateral femur for each animal. This helped to reduceanimal-to-animal variability.

[0679] The results obtained from the mechanical testing of the 4 weekpost-fracture femurs (Group C; rats 60-124) are shown in Table 2 andgraphically in FIGS. 5A-5C. p38 MAP kinase inhibitor treatmentsignificantly increased normalized peak torque relative to rofecoxibtreated rats but not relative to the control animals (FIG. 5A).Similarly, normalized torsional rigidity approached a statisticalsignificant difference between the twice-a-day p38 MAP kinase inhibitortreated rats and rofecoxib treated rats but not the control rats (FIG.5B). No significant differences were found in the normalized shearstress among the different treatment groups (FIG. 5C). TABLE 2 Summaryof Normalized Mechanical Testing Data from Rat Group C at 4 weekspost-fracture. p38 MAP Kinase p38 MAP Kinase Control Rofecoxib InhibitorInhibitor × 2 NPT 48 ± 25 32 ± 3 50 ± 11 48 ± 14 NTR 42 ± 44 19 ± 9 28 ±24 61 ± 55 NSS 14 ± 15 13 ± 9 15 ± 8  10 ± 4  Sample 7 4 5 8 Size

[0680] Mechanical testing was also performed on the femurs of rats thatwere available from Groups A and B (rats 1-57; see Appendix A).Unfortunately the number of rats available for these tests from thesegroups was too small for any statistical evaluation. However, a veryhigh normalized peak torque (˜150%) and normalized torsional rigidity(˜150%) was found in the twice-a-day p38 MAP kinase inhibitor treatedrats (see Table 3). These values are exceptionally high and are notnormally found during fracture healing in untreated rats when one canexpect to find normalized peak torque and normalized torsional rigidityvalues to reach a maximum of less than or equal to 100%. These dataagain indicate that p38 MAP kinase inhibitor treatment was acceleratingand/or enhancing fracture healing. TABLE 3 Summary of Mechanical TestingData from Rat Groups A and B. p38 MAP Kinase p38 MAP Kinase WeeksControl Rofecoxib Inhibitor Inhibitor × 2 post-fx 4 6 8 4 6 8 4 6 8 4 68 NPT 46 — — — —  57 ± 42 57  85 ± 17 — — 97 158 ± 46 NTR 43 — — — — 100± 82 69 109 ± 52 — — 126 156 ± 68 NSS 10 — — — — 16 ± 8 14.1  36 ± 11 —— 63 45 ± 1 Sample 1 — — — — 2 1 3 — — 1 2 size

[0681] Histology

[0682] The histological findings are shown in FIGS. 6A-6D, 7 and 8A-8E.At two weeks post-fracture and normal healing process in the controlgroup (FIG. 6A) was observed which was characterized by woven boneformed from the periphery of the callus towards the center followed byan area of calcified cartilage (orange in color with embeddedchondrocytes), then chondrocytes and cartilage (deep blue), withfibroblastic cells at the center of the callus. In the rofecoxib treatedanimal (FIG. 6B), less woven bone formation was observed as it did notapproach the cortical bone ends of the fracture site and an abundance ofchondrocytes. In the rat treated with the p38 MAP kinase inhibitor onceper day (FIG. 6C), a near normal amount of woven bone but more thannormal amounts of chondrocytes was observed. Finally in the rat treatedwith the p38 MAP kinase inhibitor twice per day (FIG. 6D), advancedhealing with the fracture gap almost filled with newly formed woven bonewas observed.

[0683] One potential mechanism by which the p38 MAP kinase inhibitorcould be enhancing fracture healing is by reducing osteoclast number.Osteoclasts were observed in the p38 MAP kinase inhibitor treatedfracture callus (FIG. 7). As discussed above, p 38 MAP kinase activitypositively regulates osteoclast differentiation. The number ofosteoclasts appeared to be about the same as in control animals but thisparameter was not quantified.

[0684] There were also some variations in growth plates of thecontralateral control femurs (FIGS. 8A-8E). The distal femur growthplate appeared to be normal in the control (FIG. 8A) and rofecoxib (FIG.8B) treated animals. However, in the p38 MAP kinase inhibitor treatedrats at two weeks post-fracture (FIGS. 8C and 8D), there appeared to aslight decrease in chondrocyte cell layers in the resting andproliferative zones, a decrease in the maturation of the calcificationzone, and an increase in the amount of new bone in the growth platecalcified zone, which could also be interpreted as a decrease in thecalcified zone since this was replaced with new bone. Large amounts ofnew bone formation at the growth plate of a p38 MAP kinase inhibitor(twice a day) rat at 4 weeks post-fracture and the near absence of anycalcified cartilage were observed (FIG. 8E). This suggested that p38 MAPkinase inhibitor treatment was enhancing the differentiation of thechondrocytes at the growth plate.

[0685] Materials and Methods

[0686] Animals and Drug Dosing

[0687] Retired breeder female Sprague-Dawley rats were purchased fromTaconic Farms. The rats were housed in pairs and given food and water adlibitum. A total of 124 rats were purchased for these experiments (Table4). However, only 65 rats were used for the final set of experiments asdescribed in Table 4. Drugs were first administered to the rats bygavage using PEG300 (Sigma) as a carrier (0.5 ml per kg). Rats wereinitially gavaged with drugs 6 hours after surgery (between 4 and 6 PMon day 1) and then twice/day afterwards for 5 days (between 6-8 AM andagain between 5-7 PM). Drug dosing regimes are shown in Table 5. The p38MAP kinase inhibitor used in the experiments is compound 25, Table B.Rofecoxib was obtained by pulverizing Vioxx pills (Merck). TABLE 4 RatNumber of Experimental Group Numbers Rats Variables Disposition A  1-2424   1 ml/kg PEG, See Appendix A thick rod (1.1 mm dia.) B 25-57 33 0.5ml/kg PEG, See Appendix A thick rod (1.1 mm dia.) 58 and 59  2 Roddiameter Not used for data test rats analysis C 60-124 65 0.5 ml/kg PEG,Radiographic, thin rod histological, and (0.81 mm dia.) mechanicalanalyses Total 124

[0688] TABLE 5 Drug Dosing Regimes Dose AM (6-8 AM) PM (5-7 PM) Control— PEG PEG Rofecoxib  3 mg/kg PEG Drug p38 MAP Kinase 30 mg/kg PEG DrugInhibitor-A p38 MAP Kinase 30 mg/kg Drug Drug Inhibitor-B

[0689] Fracture Production

[0690] Rats were anesthetized with a ketamine-xylazine mixture. Theright hindlimb was shaved, and cleansed with betadine. A medialparapatellar incision was made through the skin and underlying muscle tothe distal end of the femur. The patella was dislocated laterally toexpose the femoral condyles. A 20 g needle was used to drill a hole intothe distal end of the femur, between the condyles, and then used to reamthe femoral canal. A 0.81 mm diameter stainless steel wire was theninserted into the femoral condyle and tamped into the proximal end ofthe femur. The rod was then trimmed as close as possible to the femoralcondyles with wire cutters. The incision was closed in two layers withresorbable Vicryl sutures. A mid-shaft transverse fracture was made inthe right femur using a three-point bending device as describedpreviously (Bonnarens, F. and Einhorn, T. A., J. Orthop. Res. 2:97-101(1984)).

[0691] Radiography

[0692] Radiographs were made using an HP Faxitron and Kodak MINR2000mammography film. Radiographs were photographed with and Olympus C-3040digital camera for figure preparation. The 4 week post-fractureradiographs from all the rats that had survived to 4 weeks in Group C(rats 60-124) and which were not comminuted, infected, or destabilizedwere scored as follows. One point was assigned to each radiograph inwhich a cortex of the fracture callus appeared bridged and/or where thecortical bone fracture site appeared to be bridged by new bone. Thus aradiograph could have a minimal score of 0 or a maximal score of 4.

[0693] Histology

[0694] Femurs were dissected from rats at 2, 4, 6, and 8 weeks asdetailed in Appendix A. Soft tissue was dissected from the femurs andthe femurs were fixed overnight in buffered formalin. The femurs werethen embedded in polymethylmethacrylate (PMMA) following standardprocedures. Longitudinal sections (˜200 um thick) were cut from the PMMAblocks and ground and polished to a thickness of approximately 50-100um. The sections were then stained with Van Gieson's picrofuschin andStevenel's Blue. This results in dark blue to purple staining ofcartilage and lighter polychromatic blue staining of other cell typessuch as fibroblasts, osteoblasts, and osteoclasts; red staining of bone;and orange to red staining of calcified cartilage. Sections werephotographed with an Olympus BH2 microscope.

[0695] Mechanical Testing

[0696] Rats were sacrificed at 4 weeks post-fracture by CO₂asphyxiation. Rats with oblique, comminuted, or infected fractures werenot used for mechanical testing (see Appendix A). Both femora wereremoved and cleaned of all soft tissue leaving the fracture callusundisturbed and then immediately processed for mechanical testing. Thesamples were wrapped in saline soaked gauze to prevent dehydrationbetween steps. Measurements of the femora were taken using digitalcalipers to determine femur length and external callus dimensions. Theintramedullary pin was removed from the fractured femur. The femoralends were potted in 1-inch hexnuts using a low melt temperature metal(Wood's metal, Alfa Aesar, Ward Mill, Mass.). Once potted, the gagelength (L) of each femur was measured. Torsional testing was conductedusing a servohydraulic testing machine (MTS, Eden, Praire, Minn.) with a20 Nm reaction torque cell (Interface, Scottsdale, Ariz.). The testingwas carried out to failure at a rate of 2⁰/sec and a data recording rateof 20 Hz. Both the fractured and intact femora were tested in internalrotation in proper anatomic orientation. The peak torque and angle atfailure were calculated from the load-deformation curves. Internalfracture callus dimensions were measured after mechanical testing. Fromthe callus dimensions, the polar moment of inertia (J) was calculatedbased upon a hollow ellipse model (Bell, G. H. et al., J. Physiol.100:299-317 (1941); Engesaeter, L. B. et al., Acta Orthop. Scand.49:512-518 (1978)).

[0697] The equations used to derive torsional rigidity, shear stress,and J were as follows (Popov, E. P., INTRODUCTION TO MECHANICS OFSOLIDS, Englewood Cliffs, N.J., Prentice-Hall, Inc. (1968)): (i)Torsional Rigidity: (T_(max)·L)/φ where T_(max) is the peak torque valuein Nmm, L is the gage length in mm, and φ is the angle at failure inradians; (ii) Shear Stress: (T_(max)·R_(max))/J where R_(max) is thelargest radial dimension of the fracture callus in mm (a_(o)) and J isthe polar moment of inertia; (iii) Polar Moment of Inertia (J):[π(ab³+a³b−(a−t)(b−t)³−(a−t)³ (b−t)]/4 where a is[a_(i)+[(a_(o)−a_(i))/2]; b is [b_(i)+[(b_(o)−b_(i))/2]; t is theaverage bone thickness at the site of failure and is calculated as[(a_(o)−a_(i))+(b_(o)−b_(i))]/2 where a_(o) is the callus maximumoutside radius, a_(i) is the maximum interior radius, b_(o) is the leastoutside radius, and b_(i) is the least interior radius in mm. Onlytorsional testing data for which the fractured and control femur testedwithout incident were used.

[0698] Discussion

[0699] Fracture Healing and p38 MAP Kinase Inhibitor

[0700] It is evident from the experimental results that the inflammationresponse per se is not essential for successful fracture healing.However, it has not been independently corroborated that the p38 MAPkinase inhibitor dose(s) used actually reduce or eliminate the earlyinflammation response in rats following bone fracture. Assuming that p38MAP kinase inhibitor does indeed eliminate inflammation, than the dataindicate that COX-2 has essential function during fracture healing,unrelated to the initial inflammation response. The fractured femursfrom the p38 MAP kinase inhibitor treated rats had mechanical propertiessimilar or better than control animals (Tables 2 and 3, FIGS. 5A-5C),and radiographic properties significantly better that control animals(Table 1), indicating that the p38 MAP kinase inhibitor does notnegatively affect and can in fact enhance fracture healing. Conversely,even 5 days of treatment with rofecoxib negatively affected themechanical and to a lesser extent the radiographic properties of thehealing rat femur fractures. The data support a theory in which earlyCOX-2 inhibition is deleterious to fracture healing but that this is notdirectly related to a pro-inflammatory response and can in fact be moreinvolved in inflammation resolution. The p38 MAP kinase inhibitor isaccelerating and/or enhancing the fracture healing process based uponthe radiographic observations and the mechanical testing analyses atlater time points (such as 8 and 12 weeks post-fracture). Thehistological observations at two weeks post-fracture also support thiscontention (FIGS. 6A-6D). Furthermore, the p38 MAP kinase inhibitor hasno negative effect on fracture healing, unlike Celebrex or Vioxx.Therefore, the p38 MAP kinase inhibitor should be a betterpost-fracture, post-orthopedic surgical procedure analgesic and/oranti-inflammatory medication.

[0701] Potential Mechanism of Action for p38 MAP Kinase Inhibitors onFracture Healing

[0702] The following have been observed: an apparent increase in theamount of new woven bone within the callus and perhaps some morecalcified cartilage than in control rats (FIG. 7). This suggests thatthe p38 MAP kinase inhibitor acts to enhance fracture healing bypromoting chondrocyte differentiation either indirectly by promotingproliferation and/or migration of stem cells, or by inhibitingapoptosis; or directly accelerating calcified cartilage formation whichis the end stage of chondrocyte differentiation. In turn, the largeramount of calcified cartilage promotes new (woven) bone formation withinthe callus. Increased numbers of oseoblasts lining the surface of thenewly formed bone have been observed which suggest a positive effect onosteoblast function.

[0703] Again these observations are consistent with the p38 MAP kinaseinhibitor having no negative effect and in fact having a positive effecton fracture healing. In contrast, the development of fibrous non-unionsin some of the rofecoxib treated rats was observed, as observedpreviously when rats were treated continuously, instead of just 5 days,with this COX-2-selective NSAID.

Appendix A

[0704] Summary of rats used for these experiments. Rat # Drug GroupPurpose Time Point Morbidity Data OK Comments 1 Control euthanized — PEGtoxicity — saced due to poor appearance Oct. 25, 2001 2 Control mech 4wks Yes 3 Control histology 4 wks 4 Control died — PEG toxicity — Founddead @am gavaging Oct. 25, 2001 5 P38 Inhibitor histology 2 wks 6 P38Inhibitor mech 4 wks Yes 7 P38 Inhibitor euthanized — bad fx — bad fx,saced 8 P38 Inhibitor euthanized — pin slippage — Destabilized, saced 9Rofecoxib histology 8 wks 10 Rofecoxib euthanized — bad fx — bad fx,saced 11 Rofecoxib died — PEG toxicity — Found dead @pm gavaging Oct.31, 2001 12 Rofecoxib euthanized — bad fx — bad fx, saced 13 Rofecoxibmech 8 wks Yes 14 Rofecoxib mech 8 wks Yes 15 Rofecoxib mech 8 wks MTSerror No right femur fractured when placed into MTS 16 Rofecoxib mech 8wks Yes 17 P38 Inhibitor × 2 mech 8 wks Yes 18 P38 Inhibitor × 2 mech 8wks Yes 19 P38 Inhibitor × 2 died — PEG toxicity — Found dead @amgavaging Nov. 7, 2001 20 P38 Inhibitor × 2 died — PEG toxicity — Founddead @am gavaging Nov. 7, 2001 21 P38 Inhibitor × 2 mech 8 wks No poorright leg test, very high angle at failure 22 P38 Inhibitor × 2euthanized — bad fx — bad fx, saced 23 P38 Inhibitor × 2 died — PEGtoxicity — Found dead @am gavaging Nov. 7, 2001 24 P38 Inhibitor × 2died — PEG toxicity — Found dead @am gavaging Nov. 8, 2001 25 Rofecoxibeuthanized — bad fx — bad fx, saced 26 P38 Inhibitor euthanized — pinslippage — Destabilized, not harvested 27 Rofecoxib histology 4 wks 28P38 Inhibitor × 2 euthanized — bad fx — bad fx, saced 29 P38 Inhibitoreuthanized — bad fx — bad fx, saced 30 Control euthanized — bad fx — badfx, saced 31 P38 Inhibitor × 2 histology 4 wks 32 Control euthanized —bad fx — bad fx, saced 33 Control histology 4 wks 34 P38 Inhibitor mech6 wks Yes 35 Rofecoxib histology 4 wks 36 P38 Inhibitor × 2 euthanized —bad fx — bad fx, saced 37 P38 Inhibitor mech 6 wks Yes 38 P38 Inhibitoreuthanized — bad fx — bad fx, saced 39 P38 Inhibitor × 2 euthanized —pin slippage — Destabilized, not harvested 40 P38 Inhibitor × 2euthanized — surgery — knee fx during surgery, saced 41 Controlhistology 2 wks 42 P38 Inhibitor histology 2 wks pin slippage — NO PIN!,harvested 43 P38 Inhibitor × 2 histology 2 wks 44 Rofecoxib histology 2wks 45 P38 Inhibitor mech 6 wks Yes 46 P38 Inhibitor × 2 mech 6 wks Yes47 Control histology 2 wks 48 Rofecoxib euthanized — pin slippage —Destabilized, not harvested 49 Rofecoxib euthanized — — bad fx 50Rofecoxib euthanized — — bad fx 51 Rofecoxib euthanized — — bad fx 52Rofecoxib euthanized — — bad fx 53 Rofecoxib euthanized — — bad fx 54Rofecoxib euthanized — — bad fx 55 Rofecoxib euthanized — — bad fx 56Rofecoxib euthanized — — bad fx 57 Rofecoxib euthanized — — bad fx 58Pin test euthanized — — 59 Pin test euthanized — — 60 P38 Inhibitor mech4 wks Yes 61 P38 Inhibitor mech 4 wks Yes Infected?; no puss 62Rofecoxib histology 2 wks 63 Rofecoxib died — anesthetic — died duringsurgery 64 P38 Inhibitor × 2 mech 4 wks Yes 65 Control mech 4 wks Yes 66Rofecoxib euthanized — pin slippage — Destabilized, not harvested 67Control mech 4 wks Yes Almost destabilized 68 P38 Inhibitor × 2 mech 4wks Yes 69 Rofecoxib euthanized — pin slippage — Destabilized, notharvested 70 P38 Inhibitor × 2 histology 2 wks 71 P38 Inhibitorhistology 2 wks 72 Rofecoxib euthanized — pin slippage — no pin, notharvested 73 Rofecoxib histology 2 wks 74 Control histology 2 wks 75 P38Inhibitor × 2 histology 4 wks bad fx — Oblique fx 76 Control histology 4wks bad fx — Double fx 77 P38 Inhibitor × 2 histology 2 wks 78 P38Inhibitor mech 4 wks Yes 79 P38 Inhibitor histology 2 wks 80 Rofecoxibmech 4 wks No Comminuted 81 Control mech 4 wks Yes Possibly infected 82P38 Inhibitor histology 2 wks 83 P38 Inhibitor × 2 histology 4 wks badfx — Double fx 84 P38 Inhibitor mech 4 wks Yes 85 P38 Inhibitor × 2 mech4 wks Yes 86 Control histology 2 wks 87 Control mech 4 wks YesComminuted? 88 Control euthanized — surgery — pin went thru cortex,saced 89 P38 Inhibitor euthanized — bad fx — bad fx, not harvested 90P38 Inhibitor × 2 mech 4 wks Yes 91 Rofecoxib histology 2 wks 92 Controlmech 4 wks Yes Almost destabilized 93 Rofecoxib histology 2 wks 94 P38Inhibitor mech 4 wks Yes 95 P38 Inhibitor × 2 mech 4 wks Yes 96Rofecoxib mech 4 wks Yes 97 Rofecoxib mech 4 wks No left leg poor test98 Control mech 4 wks Yes 99 Control histology 2 wks 100 Controlhistology 2 wks 101 Rofecoxib histology 2 wks 102 P38 Inhibitor × 2 mech4 wks Yes 103 P38 Inhibitor euthanized — pin slippage — Destabilized,not harvested 104 Rofecoxib mech 4 wks Yes 105 P38 Inhibitor × 2histology 2 wks 106 Rofecoxib histology 2 wks 107 Rofecoxib mech 4 wksYes 108 P38 Inhibitor × 2 mech 4 wks Yes 109 Control mech 4 wks Yes 110Control euthanized — bad fx — bad fx, saced 111 P38 Inhibitor × 2euthanized — infection — Infection, not harvested 112 Rofecoxibhistology 4 wks 113 Rofecoxib euthanized — — Anethesia complications 114Control mech 4 wks Yes 115 P38 Inhibitor × 2 mech 4 wks Yes 116 P38Inhibitor euthanized — bad fx — bad fx, not harvested 117 P38 Inhibitoreuthanized — pin slippage — Destabilized, not harvested 118 Control mech4 wks Yes 119 Control euthanized — bad fx — bad fx, not harvested 120Rofecoxib Euthanized — pin slippage — Destabilized, not harvested 121P38 Inhibitor Euthanized — pin slippage — Destabilized, not harvested122 Rofecoxib Euthanized — pin slippage — Destabilized, not harvested123 Rofecoxib Mech 4 wks Yes 124 Rofecoxib Euthanized — pin slippage —Destabilized, not harvested

Example 2 p38α MAP Kinase Inhibition Improves Clinical Scores and BlocksCartilage and Bone Destruction in Early and Advanced Stages of MurineCollagen Type II Arthritis

[0705] Destruction of cartilage and bone are poorly managed hallmarks ofhuman rheumatoid arthritis (RA). p38 α MAP kinase has been shown toregulate key pro-inflammatory pathways in RA, including TNFα, IL-1β, andCOX 2. A p38α MAP kinase inhibitor (compound 162, Table B) was evaluatedto determine whether a p38 inhibitor could modulate cartilage and bonedestruction in a mouse model of RA. Induction of RA was achieved usingbovine type II cartilage (100 ug/kg, subcutaneous on days 0 and 21) andbacterial lipopolysaccharide (50 ug/mouse, intraperitoneal on day 22).

[0706] Oral treatment was vehicle alone (1% PEG 400, bid) or the p38inhibitor (90 mg/kg bid). The duration of treatment was 10 and 20 daysin mice with early onset or advanced disease, respectively. Treatmentwas initiated in mice with early onset or advanced disease. Diseasestate was determined by clinical scoring performed in a blinded protocolthat assigned a maximum per paw value of 3 based upon degree of erythemaand swelling observed. Early or advanced disease was judged by clinicalscoring, 1.6+0.6 (mean+/−std dev) on day 24 and 9.1±2.6 on day 30,respectively.

[0707] When treatment was initiated at the onset of disease, the p38inhibitor was associated with a statistically significant improvement inclinical scoring (7.0±3.4 vs 2.4±1.5 for vehicle and the p38 inhibitor,respectively, p<0.0005 by ANOVA with Bonferroni post test). Qualitativehistological evaluation included degree of bone and cartilage erosion,synovitis and pannus formation. Histological analysis showed a dramaticreduction in all aspects of joint lesion morphology including reducedcartilage and bone erosions (see, FIGS. 9A and 9B).

[0708] When treatment was initiated in mice with advanced disease therewas a significant improvement in clinical scoring (9.1±2.2 vs 4.9±1.7for vehicle and compound 25, respectively, p<0.001), reduced serumcartilage oligomeric matrix protein (COMP, a marker of cartilagebreakdown) and evidence of cartilage and bone healing (osteogensis) byhistological assessment, associated with reduced osteoclast number inthe p38 MAP kinase inhibitor group compared to the baseline (treatmentinitiation) group and the vehicle treated group (FIG. 10A, 10B, 10C and10D.

[0709] This study demonstrates that in a model of experimental arthritisassociated with significant osteolysis, p38α MAP kinase inhibition has abeneficial effect on clinical scoring and cartilage and bone destructionin early and advanced stages of the disease. Osteoclast numbers alsoappeared to be reduced by administration of a p38 MAP kinase inhibitorin this model.

[0710] All documents, e.g., scientific publications, patents and patentpublications, recited herein are hereby incorporated by reference intheir entirety to the same extent as if each individual document wasspecifically and individually indicated to be incorporated by referencein its entirety. Where the document cited only provides the first pageof the document, the entire document is intended, including theremaining pages of the document.

1. A method of promoting osteogenesis in a patient, said methodcomprising administering a pharmaceutically effective amount of a p38mitogen activated protein (MAP) kinase inhibitor to a patient in need ofosteogenesis.
 2. The method of claim 1, wherein said p38 MAP kinaseinhibitor is selected from compounds of formula:

wherein R₁ is a heteroaryl ring selected from 4-pyridyl, pyrimidinyl,quinolyl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl,1-benzimidazolyl, 4-pyridazinyl, and a 1,2,4-triazin-5-yl ring, whichheteroaryl ring is substituted one to three times with Y,N(R₁₀)C(O)R_(b), a halo-substituted mono- or di-C₁₋₆ alkyl-substitutedamino, or NHR_(a) and which ring is further optionally substituted withC₁₋₄ alkyl, halogen, hydroxyl, optionally-substituted C₁₋₄ alkoxy,optionally-substituted C₁₋₄ alkylthio, optionally-substituted C₁₋₄alkylsulfinyl, CH₂OR₁₂, amino, mono- and di-C₁₋₆ alkyl-substitutedamino, NHR_(a), N(R₁₀)C(O)R_(b), N(R₁₀)S(O)₂R_(d), or an N-heterocyclylring which has from 5 to 7 members and optionally contains an additionalheteroatom selected from oxygen, sulfur or NR₁₅; Y is X₁—R_(a); X₁ isoxygen or sulfur; R_(a) is C₁₋₆ alkyl, aryl, arylC₁₋₆ alkyl,heterocyclic, heterocyclylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆alkyl, wherein each of these moieties can be optionally substituted;R_(b) is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl,heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, or heterocyclylC₁₋₄alkyl; R_(d) is C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl,heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, or heterocyclylC₁₋₄alkyl; R₃ is hydrogen; R₄ is phenyl, naphth-1-yl, naphth-2-yl, or aheteroaryl, which is optionally substituted by one or two substituents,each of which is independently selected, and which, for a 4-phenyl,4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen,cyano, nitro, —C(Z)NR₇R₁₇, —C(Z)OR₁₆, —(CR₁₀R₂₀)_(v)COR₁₂, —SR₅, —SOR₅,—OR₁₂, halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl, -ZC(Z)R₁₂, —NR₁₀C(Z)R₁₆,or —(CR₁₀R₂₀)_(v)NR₁₀R₂₀ and which, for other positions of substitution,is halogen, cyano, —C(Z)NR₁₃R₁₄, —C(Z)OR_(f), —(CR₁₀R₂₀)_(m″)COR_(f);—S(O)_(m)R_(f), —OR_(f), —OR₁₂, halo-substituted C₁₋₄ alkyl, C₁₋₄ alkyl,—(CR₁₀R₂₀)_(m″)NR₁₀C(Z)R_(f), —NR₁₀S(O)_(m′)R₈, —NR₁₀S(O)_(m′)NR₇R₁₇,-ZC(Z)R_(f), -ZC(Z)R₁₂, or —(CR₁₀R₂₀)_(m″)NR₁₃R₁₄; R_(f) isheterocyclyl, heterocyclylC₁₋₁₀ alkyl or R₈; Z is oxygen or sulfur; v is0, 1, or 2; m is 0, 1, or 2; m′ is 1 or 2; m″ is 0, 1, 2, 3, 4, or 5; R₂is C₁₋₁₀ alkyl N₃, —(CR₁₀R₂₀)_(n′)OR₉, heterocylyl, heterocycylC₁₋₁₀alkyl, C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl,C₅₋₇cycloalkenylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,heteroarylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₁₁, (CR₁₀R₂₀)_(n)S(O)_(m)R₁₈,(CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, (CR₁₀R₂₀)_(n)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)NO₂,(CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n′)SO₂R₁₈, (CR₁₀R₂₀)_(n)S(O)_(m′)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)C(Z)R₁₁, (CR₁₀R₂₀)_(n)OC(Z)R₁₁, (CR₁₀R₂₀)_(n)C(Z)OR₁₁,(CR₁₀R₂₀)_(n)C(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)C(Z)NR₁₁OR₉,(CR₁₀R₂₀)_(n)NR₁₀C(Z)R₁₁, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)N(OR₆)C(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)N(OR₆)C(Z)R₁₁,(CR₁₀R₂₀)_(n)C(═NOR₆)R₁₁, (CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₉)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)OC(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₁₀, 5-(R₁₈)-1,2,4-oxadiazol-3-yl or4-(R₁₂)-5-(R₁₈R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl,arylalkyl, heteroaryl, heteroaryl alkyl, cycloalkyl, cycloalkyl alkyl,heterocyclic and heterocyclic alkyl groups can be optionallysubstituted; n is an integer having a value of 1 to 10; n′ is 0, or aninteger having a value of 1 to 10; R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl or NR₇R₁₇, excluding the moieties —SR₅ being—SNR₇R₁₇ and —S(O)R₅ being —SOH; R₆ is hydrogen, apharmaceutically-acceptable cation, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, aryl,arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclyl, aroyl,or C₁₋₁₀ alkanoyl; R₇ and R₁₇ are each independently selected fromhydrogen or C₁₋₄ alkyl, or R₇ and R₁₇ together with the nitrogen towhich they are attached form a heterocyclic ring of 5 to 7 members whichring optionally contains an additional heteroatom selected from oxygen,sulfur or NR₁₅; R₈ is C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl,arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₁₁,(CR₁₀R₂₀)_(n)S(O)_(m)R₁₈, (CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, or(CR₁₀R₂₀)_(n)NR₁₃R₁₄, wherein the aryl, arylalkyl, heteroaryl, andheteroaryl alkyl can be optionally substituted; R₉ is hydrogen,—C(Z)R₁₁, optionally-substituted C₁₋₁₀ alkyl, S(O)₂R₁₈,optionally-substituted aryl or optionally-substituted arylC₁₋₄ alkyl;R₁₀ and R₂₀ are each independently selected from hydrogen or C₁₋₄ alkyl;R₁₁ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl; R₁₂ is hydrogen or R₁₆; R₁₃ and R₁₄ are eachindependently selected from hydrogen or optionally-substituted C₁₋₄alkyl, optionally-substituted aryl or optionally-substituted arylC₁₋₄alkyl, or together with the nitrogen to which they are attached form aheterocyclic ring of 5 to 7 members which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or NR₉; R₁₅ is R₁₀ orC(Z)C₁₋₄ alkyl; R₁₆ is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, or C₃₋₇cycloalkyl; R₁₈ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl,arylC₁₋₁₀ alkyl, heterocyclyl, heterocyclylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl; and R₁₉ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇cycloalkyl or aryl; or a pharmaceutically-acceptable salt thereof, orwherein R₁, Y, X₁, R_(a), R_(b), R_(d), V, m, m′, m″, Z, n, n′, and R₅are defined as above, and R₂ is hydrogen, C₁₋₁₀ alkyl, halo-substitutedC₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₁₀ alkyl,heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl, (CR₁₀R₂₈)_(n)OR₂₅, (CR₁₀R₂₈)_(n′)OR₁₃, (CR₁₀R₂₈)_(n′)S(O)_(n)R₂₅,(CR₁₀R₂₈)_(n)S(O)₂R₂₅, (CR₁₀R₂₈)_(n′)NHS(O)₂R₂₅, (CR₁₀R₂₈)_(n′)NR₈R₉,(CR₁₀R₂₈)_(n′)NO₂, (CR₁₀R₂₈)_(n′)CN, (CR₁₀R₂₈)_(n′)S(O)_(n)NR₈R₉₅(CR₁₀R₂₈)_(n′)OC(Z)R₁₃, (CR₁₀R₂₈)_(n′)C(Z)OR₁₃,(CR₁₀R₂₈)_(n′)OC(Z)NR₈R₉, (CR₁₀R₂₈)_(n′)OC(Z)NR₁₃OR₁₂,(CR₁₀R₂₈)_(n′)NR₁₀C(Z)R₁₃, (CR₁₀R₂₈)_(n′)NR₁₀C(Z)NR₈R₉,(CR₁₀R₂₈)_(n′)N(OR₂₁)C(Z)NR₈R₉, (CR₁₀R₂₈)_(n′)N(OR₂₁)C(Z)R₁₃,(CR₁₀R₂₈)_(n′)OC(═NOR₂₁)R₁₃, (CR₁₀R₂₈)_(n′)NR₁₀C(═NR₂₇)NR₈R₉,(CR₁₀R₂₈)_(n′)OC(Z)NR₈R₉, (CR₁₀R₂₈)_(n′)NR₁₀C(Z)OR₁₀,(CR₁₀R₂₈)_(n′)NR₁₀C(Z)OR₁₀, 5-(R₂₅)-1,2,4-oxadiazol-3-yl or4-(R₁₂)-5-(R₁₈R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein thecycloalkyl, cycloalkyl alkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, or heterocyclylalkyl moieties can beoptionally substituted; R₃ is hydrogen or Q-(Y₁)_(t); Q is an aryl orheteroaryl group; t is 1, 2, or 3; Y₁ is independently selected fromhydrogen, C₁₋₅ alkyl, halo-substituted C₁₋₅ alkyl, halogen, or—(CR₁₀R₂₀)_(n)Y₂; Y₂ is OR₈, NO₂, S(O)_(m″)R₁₁, SR₈, S(O)_(m)OR₈,S(O)_(m)NR₈R₉, NR₈R₉, O(CR₁₀R₂₀)_(n′)NR₈R₉, C(O)R₈, CO₂R₈,CO₂(CR₁₀R₂₀)_(n′)CONR₈R₉, ZC(O)R₈, CN, C(Z)NR₈R₉, NR₁₀C(Z)R₈,C(Z)NR₈OR₉, NR₁₀C(Z)NR₈R₉, NR₁₀S(O)_(m″)R₁₁, N(OR₂₁)C(Z)NR₈R₉,N(OR₂₁)C(Z)R₈, C(═NOR₂₁)R₈, NR₁₀C(═NR₁₅)SR₁₁, NR₁₀C(═NR₁₅)NR₈R₉,NR₁₀C(═CR₁₄R₂₄)SR₁₁, NR₁₀C(═CR₁₄R₂₄)NR₈R₉, NR₁₀C(O)C(O)NR₈R₉,NR₁₀C(O)C(O)OR₁₀, C(═NR₁₃)NR₈R₉, C(═NOR₁₃)NR₈R₉, C(═NR₁₃)ZR₁₁,OC(Z)NR₈R₉, NR₁₀S(O)_(m″)CF₃, NR₁₀C(Z)OR₁₀, 5-(R₁₈)-1,2,4-oxadiazol-3-ylor 4-(R₁₂)-5-(R₁₈R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₄ is phenyl,naphth-1-yl or naphth-2-yl which is optionally substituted by one or twosubstituents, each of which is independently selected, and which, for a4-phenyl, 4-naphth-1-yl or 5-naphth-2-yl substituent, is halo, nitro,cyano, C(Z)NR₇R₁₇, C(Z)OR₂₃, (CR₁₀R₂₀)_(v)COR₃₆, SR₅, SOR₅, OR₃₆,halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl, ZC(Z)R₃₆, NR₁₀C(Z)R₂₃, or(CR₁₀R₂₀)_(v)NR₁₀R₂₀ and which, for other positions of substitution, ishalo, nitro, cyano, C(Z)NR₁₆R₂₆, C(Z)OR₈, (CR₁₀R₂₀)_(m″)COR₈,S(O)_(m)R₈, OR₈, halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl,(CR₁₀R₂₀)_(m″)NR₁₀C(Z)R₈, NR₁₀S(O)_(m′)R₁₁, NR₁₀S(O)_(m′)NR₇R₁₇, ZC(Z)R₈or (CR₁₀R₂₀)_(m″)NR₁₆R₂₆; R₇ and R₁₇ are each independently selectedfrom hydrogen or C₁₋₄ alkyl, or R₇ and R₁₇ together with the nitrogen towhich they are attached form a heterocyclic ring of 5 to 7 members,which ring optionally contains an additional heteroatom selected fromoxygen, sulfur or NR₂₂; R₈ is hydrogen, heterocyclyl, heterocyclylalkylor R₁₁; R₉ is hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl, or R₈ and R₉ can together with the nitrogen to whichthey are attached form a heterocyclic ring of 5 to 7 members, which ringoptionally contains an additional heteroatom selected from oxygen,sulfur or NR₁₂; R₁₀ and R₂₀ are each independently selected fromhydrogen or C₁₋₄ alkyl; R₁₁ is C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl,aryl, arylalkyl, heteroaryl or heteroarylalkyl; R₁₂ is hydrogen,—C(Z)R₁₃ or optionally-substituted C₁₋₄ alkyl, optionally-substitutedaryl, optionally-substituted arylC₁₋₄ alkyl, or S(O)₂R₂₅; R₁₃ ishydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or heteroaryl C₁₋₁₀ alkyl,wherein all of these moieties can be optionally substituted; R₁₄ and R₂₄are each independently selected from hydrogen, alkyl, nitro or cyano;R₁₅ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or aryl; R₁₆ and R₂₆are each independently selected from hydrogen or optionally-substitutedC₁₋₄ alkyl, optionally-substituted aryl or optionally-substitutedarylC₁₋₄ alkyl, or together with the nitrogen to which they are attachedform a heterocyclic ring of 5 to 7 members, which ring optionallycontains an additional heteroatom selected from oxygen, sulfur or NR₁₂;R₁₈ and R₁₉ are each independently selected from hydrogen, C₁₋₄ alkyl,substituted alkyl, optionally-substituted aryl, optionally-substitutedarylalkyl, or together denote an oxygen or sulfur; R₂, is hydrogen, apharmaceutically-acceptable cation, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, aryl,arylC₁₋₄ alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, orC₁₋₁₀ alkanoyl; R₂₂ is R₁₀ or C(Z)-C₁₋₄ alkyl; R₂₃ is C₁₋₄ alkyl,halo-substituted-C₁₋₄ alkyl, or C₃₋₅ cycloalkyl; R₂₅ is C₁₋₁₀ alkyl,C₃₋₇ cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl,heterocyclylC₁₋₁₀ alkyl, heteroaryl or heteroarylalkyl; R₂₇ is hydrogen,cyano, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, or aryl; R₂₈ is hydrogen, C₁₋₆alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,heteroarylC₁₋₄alkyl, heterocyclyl, or heterocyclylC₁₋₄ alkyl moiety, allof which can be optionally substituted; and R₃₆ is hydrogen or R₂₃; anda pharmaceutically acceptable salt thereof.
 3. The method of claim 1,wherein said p38 MAP kinase inhibitor is selected from the compounds ofthe formula:

and the pharmaceutically acceptable salts thereof, or a pharmaceuticalcomposition thereof, wherein

represents a single or double bond; one Z² is CA or CR⁸A and the otheris CR¹, CR¹ ₂, NR⁶ or N wherein each R¹, R⁶ and R⁸ is independentlyhydrogen or noninterfering substituent; A is —CO(X)_(j)Y wherein Y isCOR₂ or an isostere thereof and R² is hydrogen or a noninterferingsubstituent, X is a spacer of preferably 2-6 Å, and j is 0 or 1; Z³ isNR⁷ or O; each R³ is independently a noninterfering substituent; n is0-3; each of L¹ and L² is a linker; each R⁴ is independently anoninterfering substituent; m is 0-4; Z′ is CR⁵ or N wherein R⁵ ishydrogen or a noninterfering substituent; each of 1 and k is an integerfrom 0-2 wherein the sum of l and k is 0-3; Ar is an aryl groupsubstituted with 0-5 noninterfering substituents, wherein twononinterfering substituents can form a fused ring; and the distancebetween the atom of Ar linked to L² and the center of the a ring ispreferably 4.5-24 Å.
 4. The method of claim 1, wherein said p38 MAPkinase inhibitor is selected from the compounds of the formula:

wherein A is (a)

wherein R³′, R⁴′, R⁵′ are each independently H, C₁₋₁₀-alkyl, optionallysubstituted by halogen up to perhalo, C₁₋₁₀ alkoxy, optionallysubstituted by halogen, up to perhaloalkoxy, halogen; NO₂ or NH₂; R⁶′ isH, C₁₋₁₀-alkyl, C₁₋₁₀ alkoxy, —NHCOR¹; —NR¹COR¹; NO₂;

one of R^(4′), R^(5′), or R^(6′) can be —X-Y; or 2 adjacentR^(4′)-R^(6′) can together be an aryl or heteroaryl ring with 5-12atoms, optionally substituted by C₁₋₁₀-alkyl, C₁₋₁₀ alkoxy, C₃₋₁₀cycloalkyl, C₂₋₁₀ alkenyl, C₁₋₁₀ alkanoyl, C₆₋₁₂ aryl, C₅₋₁₂ heteroarylor C₆₋₁₂ arakyl; R¹ is C₁₋₁₀-alkyl optionally substituted by halogen, upto perhalo; X is —CH₂—, —S—, —N(CH₃)—, —NHC(O)—, —CH₂—S—, —S—CH₂—,—C(O)—, or —O—; X is additionally a single bond where Y is pyridyl; Y isphenyl, pyridyl, naphthyl, pyridone, pyrazine, benzodioxane,benzopyridine, pyrimidine or benzothiazole, each optionally substitutedby C₁₋₁₀-alkyl, C₁₋₁₀-alkoxy, halogen, OH, —SCH₃ or NO₂ or, where Y isphenyl, by

and a pharmaceutically-acceptable salt thereof; or (b)

wherein R¹ is selected from the group consisting of C₃-C₁₀ alkyl, C₃-C₁₀cycloalkyl, up to per-halo substituted C₁-C₁₀ alkyl and up toper-halosubstituted C₃-C₁₀ cycloalkyl; and R² is C₆-C₁₄ aryl, C₃-C₁₄heteroaryl, substituted C₆-C₁₄ aryl or substituted C₃-C₁₄ heteroaryl;wherein if R² is a substituted group, it is preferably substituted byone or more substituents independently selected from the groupconsisting of halogen, up to per-halosubstitution, and V_(n), wheren=0-3 and each V is independently selected from the group consisting of—CN, —OC(O)NR⁵R^(5′), —CO₂R⁵, —C(O)NR⁵R^(5′), —OR⁵, —SR⁵, —NR⁵R^(5′),—C(O)R⁵, —NR⁵C(O)OR^(5′), —SO₂R⁵—SOR⁵, —NR⁵C(O)R^(5′), —NO₂, C₁-C₁₀alkyl, C₃-C₁₀ cycloalkyl, C₆-C₁₄ aryl, C₃-C₁₃ heteroaryl, C₇-C₂₄alkaryl, C₄-C₂₄ alkheteroaryl, substituted C₁-C₁₀ alkyl, substitutedC₃-C₁₀ cycloalkyl, substituted C₆-C₁₄ aryl, substituted C₃-C₁₃heteroaryl, substituted C₇-C₂₄ alkaryl and substituted C₄-C₂₄alkheteroaryl; wherein if V is a substituted group, it is substituted byone or more substituents independently selected from the groupconsisting of halogen, up to per-halosubstitution, —CN, —CO₂R⁵, —C(O)R⁵,—C(O)NR⁵R^(5′), —NR⁵R^(5′), —OR⁵, —SR⁵, —NR⁵C(O)R^(5′), —NR⁵C(O)OR^(5′)and —NO₂; and R⁵ and R^(5′) are independently selected form the groupconsisting of H, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₆-C₁₄ aryl, C₃-C₁₃heteroaryl, C₇-C₂₄ alkaryl, C₄-C₂₃ alkheteroaryl, up toper-halosubstituted C₁-C₁₀ alkyl, up to per-halosubstituted C₃-C₁₀cycloalkyl, up to per-halosubstituted C₆-C₁₄ aryl and up toper-halosubstituted C₃-C₁₃ heteroaryl; and a pharmaceutically-acceptablesalt thereof; or (c) a substituted moiety of up to 40 carbon atoms ofthe formula: -L-(M-L¹)_(q), where L is a 5- or 6-membered cyclicstructure bound directly to D, L¹, comprises a substituted cyclic moietyhaving at least 5 members, M is a bridging group having at least oneatom, q is an integer of from 1-3; and each cyclic structure of L and L¹contains 0-4 members of the group consisting of nitrogen, oxygen andsulfur; L¹ is substituted by at least one substituent selected from thegroup consisting of —SO₂R_(x), —C(O)R_(x) and —C(NR_(y))R_(z); R_(y) ishydrogen or a carbon-based moiety of up to 24 carbon atoms optionallycontaining heteroatoms selected from N, S and O and optionallyhalosubstituted, up to perhalo; R_(z) is hydrogen or a carbon-basedmoiety of up to 30 carbon atoms optionally containing heteroatomsselected from N, S and O and optionally substituted by halogen, hydroxyand carbon-based substituents of up to 24 carbon atoms, which optionallycontain heteroatoms selected from N, S and O and are optionallysubstituted by halogen; and R_(x) is R_(z) or NR_(a)R_(b) where R_(a)and R_(b) are i) independently hydrogen, a carbon-based moiety of up to30 carbon atoms optionally containing heteroatoms selected from N, S andO and optionally substituted by halogen, hydroxy and carbon-basedsubstituents of up to 24 carbon atoms, which optionally containheteroatoms selected from N, S and O and are optionally substituted byhalogen, or —OSi(R_(f))₃ where R_(f) is hydrogen or a carbon-basedmoiety of up to 24 carbon atoms optionally containing heteroatomsselected from N, S and O and optionally substituted by halogen, hydroxyand carbon-based substituents of up to 24 carbon atoms, which optionallycontain heteroatoms selected from N, S and O and are optionallysubstituted by halogen; or ii) R_(a) and R_(b) together form a 5-7member heterocyclic structure of 1-3 heteroatoms selected from N, S andO, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatomsselected from N, S and O, substituted by halogen, hydroxy orcarbon-based substituents of up to 24 carbon atoms, which optionallycontain heteroatoms selected from N, S and O and are optionallysubstituted by halogen; or iii) one of R_(a) or R_(b) is —C(O)—, a C₁-C₅divalent alkylene group or a substituted C₁-C₅ divalent alkylene groupbound to the moiety L to form a cyclic structure with at least 5members, wherein the substituents of the substituted C₁-C₅ divalentalkylene group are selected from the group consisting of halogen,hydroxy, and carbon-based substituents of up to 24 carbon atoms, whichoptionally contain heteroatoms selected from N, S and O and areoptionally substituted by halogen; and a pharmaceutically-acceptablesalt thereof; and B is an unsubstituted or substituted, up to tricyclic,aryl or heteroaryl moiety with up to 30 carbon atoms with at least one5- or 6-membered aromatic structure containing 0-4 members of the groupconsisting of nitrogen, oxygen and sulfur; wherein if B is substituted,it is substituted by one or more substituents selected from the groupconsisting of halogen, up to per-halo, and W_(n), wherein n is 0-3 andeach W is independently selected from the group consisting of —CN,—CO₂R⁷, —C(O)NR⁷R⁷, —C(O)R⁷, —NO₂, —OR⁷, —SR⁷, —NR⁷R⁷, —NR⁷C(O)OR⁷,—NR⁷C(O)R⁷, C₁-C₁₀ alkyl, C₂₋₁₀-alkenyl, C₁-₁₀-alkoxy, C₃-C₁₀cycloalkyl, C₆-C₁₄ aryl, C₇-C₂₄ alkaryl, C₃-C₁₃ heteroaryl, C₄-C₂₃alkheteroaryl, substituted C₁-C₁₀ alkyl, substituted C₂₋₁₀-alkenyl,substituted C₁-₁₀-alkoxy, substituted C₃-C₁₀ cycloalkyl, substitutedC₄-C₂₃ alkheteroaryl and -Q-Ar; wherein if W is a substituted group, itis substituted by one or more substituents independently selected fromthe group consisting of —CN, —CO₂R⁷, —C(O)NR⁷R⁷, —C(O)R⁷, —NO₂, —OR⁷,—SR⁷, —NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷ and halogen up to per-halo;wherein each R⁷ is independently selected from H, C₁-C₁₀ alkyl,C₂-₁₀-alkenyl, C₃-C₁₀ cycloalkyl, C₆-C₁₄ aryl, C₃-C₁₃ heteroaryl, C₇-C₂₄alkaryl, C₄-C₂₃ alkheteroaryl, up to per-halosubstituted C₁-C₁₀ alkyl,up to per-halosubstituted C₂-₁₀-alkenyl, up to per-halosubstitutedC₃-C₁₀ cycloalkyl, up to per-halosubstituted C₆-C₁₄ aryl and up toper-halosubstituted C₃-C₁₃ heteroaryl; wherein Q is —O—, —S—, —N(R)⁷,—(CH₂)—_(m), —C(O)—, —CH(OH)—, —NR⁷C(O)NR⁷R⁷—, —NR⁷C(O)—, —C(O)NR⁷—,—(CH₂)_(m)O—, —(CH₂)_(m)S—, —(CH₂)_(m)N(R⁷)—, —O(CH₂)_(m)—, —CHX^(a),—CX^(a) ₂—, —S—(CH₂)_(m)— and —N(R⁷)(CH₂)_(m)—, where m=1-3, and X^(a)is halogen; and Ar′ is a 5-10 member aromatic structure containing 0-4members of the group consisting of nitrogen, oxygen and sulfur, which isunsubstituted or substituted by halogen up to per-halosubstitution andoptionally substituted by Z_(n1), wherein n1 is 0 to 3 and each Zsubstituent is independently selected from the group consisting of —CN,—CO₂R⁷, —C(O)NR⁷R⁷, —C(O)—NR⁷, —NO₂, —OR⁷, —SR⁷, —NR⁷R⁷, —NR⁷C(O)OR⁷,—C(O)R⁷, —NR⁷C(O)R⁷, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₆-C₁₄ aryl,C₃-C₁₃ heteroaryl, C₇-C₂₄ alkaryl, C₄-C₂₃ alkheteroaryl, substitutedC₁-C₁₀ alkyl, substituted C₃-C₁₀ cycloalkyl, substituted C₇-C₂₄ alkaryland substituted C₄-C₂₃ alkheteroaryl; wherein the one or moresubstituents of Z are independently selected from the group consistingof —CN, —CO₂R⁷, —C(O)NR⁷R⁷, —OR⁷, —SR⁷, —NO₂, —NR⁷R⁷, —NR⁷C(O)R⁷ and—NR⁷C(O)OR⁷; and a pharmaceutically-acceptable salt thereof.
 5. Themethod of claim 1, wherein said patient is in need of treatment of bonefracture.
 6. The method of claim 5, wherein said patient has a traumaticbone fracture or a long-term bone fracture.
 7. The method of claim 1,wherein said patient is in need of enhanced bone grafting.
 8. The methodof claim 1, wherein said patient is in need of treatment of a bonedisease.
 9. The method of claim 8, wherein the bone disease is selectedfrom the group consisting of arthritis, osteoarthritis, andosteoporosis.
 10. The method of claim 1, wherein said p38 MAP kinaseinhibitor is selective for p38α, p38β, p38γ, or p38δ.
 11. The method ofclaim 1, wherein said patient is in need of decreased bone resorption.12. The method of claim 1, wherein said patient is a human.
 13. Themethod of claim 1, wherein administration of said p38 MAP kinaseinhibitor decreases osteoclast numbers.
 14. A method of enhancing bonehealing following facial reconstruction, maxillary reconstruction,mandibular reconstruction, periodontal disease or tooth extraction,enhancing long bone extension, enhancing prosthetic ingrowth orincreasing bone synostosis in a patient, said method comprisingadministering a therapeutically effective amount of a p38 mitogenactivated protein (MAP) kinase inhibitor to a patient in need of thesame.
 15. The method of claim 14, wherein said patient is a human.
 16. Amethod of increasing bone mass in a mammal, said method comprisingadministering a therapeutically effective amount of a p38 mitogenactivated protein (MAP) kinase inhibitor to a mammal in need ofincreased bone mass.
 17. A method of increasing chondrocytedifferentiation in a mammal, said method comprising administering atherapeutically effective amount of a p38 mitogen activated protein(MAP) kinase inhibitor to a mammal in need of increased chondrocytedifferentiation.
 18. A method of accelerating cartilage formation in amammal, said method comprising administering a therapeutically effectiveamount of a p38 mitogen activated protein (MAP) kinase inhibitor to amammal in need of accelerated cartilage formation.